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14 Kidney and genitourinary disease 575-640

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14 Kidney and genitourinary disease
A.N. TURNER
J. SAVILL
L.H. STEWART
A. CUMMING
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FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
Renal medicine ranges from the management of common conditions (e.g. urinary tract infection) to the use of complex technology to replace renal function. Since it has been possible to do this, the practice of nephrology has extended to involve the management of multisystem diseases where renal function is threatened or lost, and to transplantation, by which loss of renal function is most effectively replaced.
In health, the volume and composition of body fluids are tightly regulated and the kidneys are largely responsible for maintaining this state. This is achieved by making large volumes of an ultrafiltrate of plasma (120 ml/min, 170 l/day) at the glomerulus, and selectively reabsorbing components of the ultrafiltrate at points along the nephron. Most of these processes are tightly controlled and many represent the targets of drug action.
In addition, the kidney has a number of hormonal functions. Three of these are particularly important:
The kidney is the main source of erythropoietin, which is produced by interstitial peritubular cells in response to hypoxia. Replacement of erythropoietin reverses the anaemia of chronic renal failure.
The kidney is essential for vitamin D metabolism; it hydroxylates 25-hydroxycholecalciferol to the active form, 1,25-dihydroxycholecalciferol. Failure of this process contributes to the hypocalcaemia and bone disease of chronic renal failure (see p. 601).
Renin is secreted from the juxtaglomerular apparatus in response to reduced afferent arteriolar pressure, stimulation of sympathetic nerves, and changes in the composition of fluid in the distal convoluted tubule at the macula densa. Renin generates angiotensin II. As well as causing constriction of the efferent arteriole of the glomerulus and, thereby increasing glomerular filtration pressure (see Fig. 14.1), this produces systemic vasoconstriction and hypertension. Thus renal ischaemia leads to systemic hypertension.





Integration link: Basis of glomerular filtration

Taken from Physiology 2e








Integration link: Renin-angiotensin-aldosterone system

Taken from Physiology 5e




FUNCTIONAL ANATOMY
KIDNEYS
Adult kidneys are 11-14 cm (three lumbar vertebral bodies) in length, and are located retroperitoneally on either side of the aorta and inferior vena cava. The right kidney is usually a few centimetres lower because the liver lies above it. Both kidneys rise and descend several centimetres with respiration.
Each kidney contains approximately 1 million nephrons. There is a rich blood supply (20-25% of cardiac output) although there is considerable physiological variation in this. Intralobular branches of the renal artery give rise to the glomerular afferent arterioles. Variations in the calibre of the afferent and efferent arterioles control the filtration pressure at the glomerular basement membrane (GBM). This is normally tightly regulated in order to maintain a constant glomerular filtration rate (GFR) despite varying systemic blood pressure and renal perfusion pressure. In response to a reduction in perfusion pressure, constriction of the efferent arteriole restores filtration pressure. The efferent arteriole's response is dependent on angiotensin II production. The efferent arteriole goes on to supply the distal nephron and medulla.
The glomerulus contains three main cell types (see Fig. 14.1D). The GBM is produced by fusion of the basement membranes of epithelial and endothelial cells. Both of these cells are specialised in structure and function. The glomerular capillary endothelial cells contain pores (fenestrae) which allow access of circulating molecules to the underlying GBM. On the outer side of the GBM, glomerular epithelial cells (podocytes) put out multiple long foot processes which interdigitate with those of adjacent epithelial cells. These are non-dividing cells whose integrity is critical to the structure and function of the glomerulus. The death of a podocyte may lead to adhesion of the underlying GBM to Bowman's capsule, followed by the formation of a focal glomerular scar. The normal filtration barrier (see Fig. 14.1E) requires integrity of the junctions between the epithelial cells, the epithelial slit diaphragm apparatus, as well as the GBM itself, and these structures are responsible for the size limit to glomerular filtration. The filtration barrier at the glomerulus is normally almost absolute to proteins the size of albumin (67 kDa) or larger, with those of 20 kDa or smaller able to filter freely. Between these sizes there is a gradient of clearance, the behaviour of individual molecules being influenced by their shape and charge. Anionic (negatively charged) proteins are relatively less freely filtered than cationic proteins. Little lipid is filtered.
Mesangial cells lie in the central region of the glomerulus. They have similarities to vascular smooth muscle cells (e.g. contractility), but also some macrophage-like properties. In health, bone marrow-derived macrophages are occasionally found in glomeruli and in the interstitium.
Tubular cells are polarised, with a brush border (proximal tubular cells) and specialised functions at both their basal and their apical surfaces. Regionally, in the proximal convoluted tubule (PCT), thick ascending limb of the loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD) they serve distinct functions, and carry a specific complement of transporter, channel and receptor molecules (see Fig. 9.3, p. 274). Interstitial cells between tubules are less well understood. Fibroblast-like cells in the cortex are capable of producing erythropoietin in response to hypoxia. In the medulla, lipid-laden interstitial cells are believed to be important in prostaglandin production.
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Figure 14.1 Functional anatomy of the kidney. A Anatomical relationships of the kidney. B A single nephron. For the functions of different segments, see Figure 9.3, page 274. C Histology of a normal glomerulus. D Schematic cross-section of a glomerulus showing five capillary loops, to illustrate structure and show cell types. E Electron micrograph of the filtration barrier. (GBM = glomerular basement membrane)
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Figure 14.2 Endoscopic views of the upper and lower urinary tract.
COLLECTING SYSTEM AND LOWER URINARY TRACT
This part of the urinary system is illustrated in Figure 14.2. It is subject to a variety of congenital anomalies, as outlined on page 608.
CONTINENCE MECHANISMS
Continence is dependent on the anatomical structures shown in Figure 14.2 and also on neurological and muscle (sphincter and detrusor) function. Parasympathetic nerves arising from S2-4 supply the detrusor muscle. These cholinergic nerves stimulate detrusor contraction, resulting in micturition. Sympathetic nerves arising from T10-L2 relay in the pelvic ganglia before reaching the detrusor and bladder neck. Stimulation of these noradrenergic nerves produces detrusor relaxation (via ß-adrenoceptors) and contraction of the bladder neck (via a-adrenoceptors). This assists urine storage and continence during bladder filling. The distal sphincter mechanism is innervated from the sacral segments S2-4 by somatic motor fibres which reach the sphincter either by the pelvic plexus or via the pudendal nerves.
Afferent sensory impulses pass to the cerebral cortex which suppresses detrusor contractions. Their main function is to inhibit micturition until it is appropriate.
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Figure 14.3 Normal micturition cycle.
The micturition cycle
Storage (filling) phase
Due to the high compliance of the detrusor muscle the bladder fills steadily without a rise in intravesical pressure. As bladder volume increases, stretch receptors in its wall cause reflex bladder relaxation and increased sphincter tone. At approximately 75% bladder capacity there is a desire to void. Voluntary control is now exerted over the desire to void, which disappears temporarily. Compliance of the detrusor allows further increase in capacity until the next desire to void. Just how often this desire needs to be inhibited depends on many factors, not the least of which is finding a suitable place in which to void.
Voiding (micturition) phase
The act of micturition is initiated first by voluntary and then by reflex relaxation of the pelvic floor and distal sphincter mechanism, followed by reflex detrusor contraction. These actions are coordinated by the pontine micturition centre. Intravesical pressure remains greater than urethral pressure until the bladder is empty. Disorders of micturition may therefore be structural or neurogenic.
The normal micturition cycle is illustrated in Figure 14.3.
INVESTIGATION OF RENAL AND URINARY TRACT DISEASE
TESTS OF FUNCTION


Figure 14.4 Factors affecting blood levels of urea and creatinine. Factors affecting intake and production are shown to the left ('in'); those affecting excretion are shown to the right ('out'). Creatinine intake is omitted here as dietary creatinine (from meat) only rarely influences blood levels.
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14.1 GLOMERULAR FILTRATION RATE (GFR)
The GFR is the rate at which fluid passes into nephrons after filtration at the glomerulus, and is a measure of the overall function of the kidney. Its normal range depends on the size of an individual, so GFR is often reported after normalisation for surface area-typically 1.73 m2. About 95% of the normal population have values within these limits. Average values for men are 12% higher than those for women:


Measuring clearance to estimate GFR
Most solutes are reabsorbed from or additionally secreted into renal tubules, so simple measurements of their concentration in urine or blood do not give reliable information about glomerular filtration. Inulin is an example of a substance that is freely filtered and not altered by tubular function, but measurements of clearance are difficult. Disappearance of trace amounts of radio-labelled ethylenediamine-tetraacetic acid (EDTA) from the blood can be measured more simply
Creatinine clearance (CrCl) is relatively simple to measure, as no injections are required; measurements of serum concentration and the amount of creatinine in a 24-hour urine collection are needed. It is calculated as follows (care with units is required:
However, CrCI exaggerates GFR when renal function is poor and may be affected by drugs that alter tubular creatinine secretion (e.g. trimethoprim, cimetidine). Its reliability also depends on accurate urine collection
Equations
Equations have been shown to be a reliable and consistent way of assessing GFR from serum creatinine alone. The Cockcroft and Gault equation is widely used, and is reasonably accurate at normal to moderate renal function. However, it was designed to estimate CrCl, not GFR. Better equations have been developed for poorer levels of function (e.g. creatinine > 180 µmol/l):
The Modification of Diet in Renal Disease (MDRD) study equation is particularly well proven in 'standard' patients at varying levels of renal function but is complex; calculators are available on-line (see Further information, p. 639) or on portable electronic devices. It is unwise to expect any of these equations to perform well in unusual circumstances, such as extremes of body mass


Blood urea is a poor guide to renal function as it varies with protein intake, liver metabolic capacity and renal perfusion (see Fig. 14.4). Serum creatinine is a more reliable guide as it is produced from muscle at a constant rate and almost completely filtered at the glomerulus. As very little creatinine is secreted by tubular cells, the creatinine clearance provides a reasonable approximation of the glomerular filtration rate (see Box. 14.1). If muscle mass remains constant, changes in creatinine concentration reflect changes in GFR. However, an increase outside the normal range is typically not seen until GFR is reduced by about 50% (see Fig. 14.5), and isolated measurements of creatinine give a misleading impression of renal function in those with unusually small amounts (and occasionally in those with very large amounts) of muscle. More accurate measurement of GFR is now most easily undertaken by ascertaining the clearance of 51Cr-labelled ethylenediamine-tetraacetic acid (EDTA). This has largely replaced estimation of inulin clearance in clinical practice.


Figure 14.5 Serum creatinine and the glomerular filtration rate (GFR).
The inverse reciprocal relationship between GFR and serum creatinine is shown for a group of patients with renal disease. The red band indicates the range of values obtained. Note that some individuals have a GFR as low as 30-40 ml/min without serum creatinine rising out of the normal range.
Tests of tubular function, including concentrating ability, ability to excrete a water load and ability to excrete acid, are valuable in some circumstances.
IMAGING TECHNIQUES
Plain radiographs may show the renal outlines if perinephric fat and bowel gas shadows permit. Opaque calculi and calcification within the renal tract may also be shown.
Ultrasound
This quick, non-invasive technique is the first and often the only method required for renal imaging. It can show renal size and position, dilatation of the collecting system (suggesting obstruction, see Fig. 14.6), distinguish tumours and cysts, and show other abdominal, pelvic and retroperitoneal pathology. In addition, it can image the prostate and bladder, and estimate completeness of emptying in suspected bladder outflow obstruction. Images are often less clear in obese individuals. Ultrasonographic density of the renal cortex is increased and corticomedullary differentiation lost in chronic renal disease.
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Figure 14.6 Renal ultrasound. A Normal kidney. The normal cortex is less echo-dense (blacker) than the adjacent liver. B A simple cyst occupies the upper pole of an otherwise normal kidney. C The renal pelvis and calyces are dilated by a chronic obstruction to urinary outflow. The thinness and increased density of the remaining renal cortex indicate chronicity.
Doppler techniques are used to show blood flow and its characteristics in extrarenal and larger intrarenal vessels. The resistivity index is the ratio of peak systolic and diastolic velocities, and is influenced by the resistance to flow through small intrarenal arteries. It may be elevated in various diseases, including acute glomerulonephritis and rejection of a renal transplant. While severe renal artery stenosis causes damping of flow in intrarenal vessels, with high peak velocities, to date ultrasound has not proved to be a reliable technique for detecting renal artery stenosis.
The disadvantages of renal ultrasound are that it is operator-dependent and that the printed images convey only a fraction of the information gained by performing the investigation in real time.
Intravenous urography (IVU)


Figure 14.7 Intravenous urograms. A Nephrogram phase at 1 minute. B Collecting system at 5 minutes. C Intravenous urogram showing a later view of a normal collecting system on the patient's left, with obstruction of the right system by a transitional cell carcinoma of the upper ureter, shown as a filling defect (arrow).
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14.2 RENAL COMPLICATIONS OF RADIOLOGICAL INVESTIGATIONS
Contrast nephrotoxicity
An acute deterioration in renal function, sometimes life-threatening, commencing within 24 hrs of administration of i.v. radiographic contrast media
Risk factors
Pre-existing renal impairment
Use of high-osmolality contrast media
Diabetes mellitus-especially if treated with metformin
Myeloma
Prevention
Hydration-e.g. free oral fluids plus i.v. isotonic saline 500 ml then 250 ml/hr during procedure
Avoid nephrotoxic drugs; withhold non-steroidal anti-inflammatory drugs (NSAIDs); omit metformin for 48 hrs
Most other measures are ineffective or increase (e.g. diuretics) the risk
If the risks are high, consider alternative methods of imaging
Cholesterol atheroembolism
Typically follows days to weeks after intra-arterial investigations-see page 611


While intravenous urography has been largely replaced by ultrasound for routine renal imaging, this technique provides excellent definition of the collecting system and ureters, and remains superior to ultrasound for examining renal papillae, stones and urothelial malignancy (see Fig. 14.7). Radiographs are taken at intervals following administration of an intravenous bolus of an iodine-containing compound that is excreted by the kidney. An early image (1 minute after injection) will demonstrate the nephrogram phase of renal perfusion in patients with an adequate renal arterial supply. This is followed by contrast filling the collecting system, ureters and bladder. The disadvantages of this technique are the need for an injection, time requirement, dependence on adequate renal function for good images, and risk of exposure to contrast medium (see Box 14.2).
Pyelography
Pyelography (direct injection of contrast medium into the collecting system from above or below) offers the best views of the collecting system and upper tract, and is commonly used to identify the cause of urinary tract obstruction (see p. 590). Antegrade pyelography requires the insertion of a fine needle into the pelvicalyceal system under ultrasound or radiographic control. Contrast is injected to outline the collecting system, and particularly to localise the site of obstruction. This approach is much more difficult and hazardous in a non-obstructed kidney. In the presence of obstruction, percutaneous nephrostomy drainage can be established, and often stents can be passed through any obstruction. Retrograde pyelography can be performed by inserting catheters into the ureteric orifices at cystoscopy (see Fig. 14.8).
Renal arteriography and venography
The main indication for renal arteriography is to investigate suspected renal artery stenosis (see p. 609) or haemorrhage. In the absence of computed tomography it is also valuable for defining renal tumours. Therapeuticballoon dilatation and stenting of the renal artery may be undertaken, and bleeding vessels or arteriovenous fistulae occluded.
Computed tomography (CT)


Figure 14.8 Retrograde pyelography. The best views of the normal collecting system are shown by pyelography. A catheter has been passed into the left renal pelvis at cystoscopy. The anemone-like calyces are sharp-edged and normal. (Compare with the obstructed system shown in Figure 14.7C.)
While not routinely of greater value than ultrasound, CT is particularly useful for characterising mass lesions within the kidney (see Fig. 14.40, p. 635), or combinations of cysts with masses. It gives clearer definition of the retroperitoneal anatomy and, unlike ultrasound, is aided by increased amounts of fat.
Spiral CT is a rapid-sequence technique, with images obtained immediately following a large bolus injection of intravenous contrast media to outline vascular structures. It produces high-quality images of the main renal vessels and, when used to screen for possible renal artery stenosis in secondary hypertension, has the advantage of providing renal and adrenal images at the same time. It is also a very useful technique for demonstrating renal stones.
Magnetic resonance imaging (MRI)
MRI offers excellent resolution and distinction between different tissues. Magnetic resonance angiography (MRA) uses gadolinium-based contrast media which are non-nephrotoxic, and avoids the risk of atheroemboli. It can produce good images of main renal vessels. These techniques are likely to develop further and find an important role in non-invasive screening for renal artery stenosis. The relative places of spiral CT and MRA for this condition have yet to be defined.
SPECIAL TESTS
Radionuclide studies
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Figure 14.9 DMSA isotope renogram. A posterior view is shown of a normal left kidney and a small right kidney (with evidence of cortical scarring at upper and lower poles) which contributes only 39% of total renal function.
These studies require the injection of gamma ray-emitting radiopharmaceuticals which are taken up and excreted by the kidney, a process which can be monitored by an external gamma camera. In this way, the function of individual kidneys can be assessed.
Diethylenetriamine-pentaacetic acid labelled with technetium (99mTc-DTPA) is excreted by glomerular filtration. Following injection of DTPA, computer analysis of uptake and excretion can be used to provide information regarding the arterial perfusion of each kidney. In renal artery stenosis, transit time is prolonged, peak activity delayed and excretion reduced. In less severe but still significant stenosis, a single dose of an angiotensin-converting enzyme (ACE) inhibitor ('captopril renography') can, by inhibiting the compensatory efferent glomerular arteriolar constriction induced by angiotensin II, induce these changes in a kidney that previously perfused normally, although this is not a reliable enough technique for screening. In patients with significant obstruction of the outflow tract, persistence of the nuclide in the renal pelvis is seen (see Fig. 14.12, p. 591), and a loop diuretic fails to accelerate its disappearance.
Dimercaptosuccinic acid labelled with technetium (99mTc-DMSA) is filtered by glomeruli and partially bound to proximal tubular cells. Following intravenous injection, images of the renal cortex show the shape, size and function of each kidney (see Fig. 14.9). This is a sensitive method of demonstrating early cortical scarring that is of particular value in children with vesico-ureteric reflux and pyelonephritis. It is also possible to assess the relative contribution of each kidney to total function.
Renal biopsy
Renal biopsy is used to establish the nature and extent of renal disease in order to judge the prognosis and need for treatment. The indications, contraindications and complications are given in Box 14.3. The procedure is performed with ultrasound guidance to ensure accurate needle placement into a renal pole. Radiographic screening after contrast administration or other methods may also be used. Light microscopy, electron microscopy and immunohistological assessment of the specimen may all be required.
14.3 RENAL BIOPSY
Indications
Acute renal failure that is not adequately explained
Chronic renal failure with normal-sized kidneys
Nephrotic syndrome or glomerular proteinuria in adults
Nephrotic syndrome in children that has atypical features or is not responding to treatment
Isolated haematuria with renal characteristics or associated abnormalities

Contraindications
Disordered coagulation or thrombocytopenia
Uncontrolled hypertension
Kidneys < 60% predicted size
Solitary kidney (except transplants) (relative contraindication)

Complications
Pain, usually mild
Bleeding into urine, usually minor but may produce clot colic and obstruction
Bleeding around the kidney, occasionally massive and requiring angiography with intervention, or surgery
Arteriovenous fistula, rarely clinically significant


pages 575 - 585


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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
Renal medicine ranges from the management of common conditions (e.g. urinary tract infection) to the use of complex technology to replace renal function. Since it has been possible to do this, the practice of nephrology has extended to involve the management of multisystem diseases where renal function is threatened or lost, and to transplantation, by which loss of renal function is most effectively replaced.
In health, the volume and composition of body fluids are tightly regulated and the kidneys are largely responsible for maintaining this state. This is achieved by making large volumes of an ultrafiltrate of plasma (120 ml/min, 170 l/day) at the glomerulus, and selectively reabsorbing components of the ultrafiltrate at points along the nephron. Most of these processes are tightly controlled and many represent the targets of drug action.
In addition, the kidney has a number of hormonal functions. Three of these are particularly important:
The kidney is the main source of erythropoietin, which is produced by interstitial peritubular cells in response to hypoxia. Replacement of erythropoietin reverses the anaemia of chronic renal failure.
The kidney is essential for vitamin D metabolism; it hydroxylates 25-hydroxycholecalciferol to the active form, 1,25-dihydroxycholecalciferol. Failure of this process contributes to the hypocalcaemia and bone disease of chronic renal failure (see p. 601).
Renin is secreted from the juxtaglomerular apparatus in response to reduced afferent arteriolar pressure, stimulation of sympathetic nerves, and changes in the composition of fluid in the distal convoluted tubule at the macula densa. Renin generates angiotensin II. As well as causing constriction of the efferent arteriole of the glomerulus and, thereby increasing glomerular filtration pressure (see Fig. 14.1), this produces systemic vasoconstriction and hypertension. Thus renal ischaemia leads to systemic hypertension.





Integration link: Basis of glomerular filtration

Taken from Physiology 2e








Integration link: Renin-angiotensin-aldosterone system

Taken from Physiology 5e




FUNCTIONAL ANATOMY
KIDNEYS
Adult kidneys are 11-14 cm (three lumbar vertebral bodies) in length, and are located retroperitoneally on either side of the aorta and inferior vena cava. The right kidney is usually a few centimetres lower because the liver lies above it. Both kidneys rise and descend several centimetres with respiration.
Each kidney contains approximately 1 million nephrons. There is a rich blood supply (20-25% of cardiac output) although there is considerable physiological variation in this. Intralobular branches of the renal artery give rise to the glomerular afferent arterioles. Variations in the calibre of the afferent and efferent arterioles control the filtration pressure at the glomerular basement membrane (GBM). This is normally tightly regulated in order to maintain a constant glomerular filtration rate (GFR) despite varying systemic blood pressure and renal perfusion pressure. In response to a reduction in perfusion pressure, constriction of the efferent arteriole restores filtration pressure. The efferent arteriole's response is dependent on angiotensin II production. The efferent arteriole goes on to supply the distal nephron and medulla.
The glomerulus contains three main cell types (see Fig. 14.1D). The GBM is produced by fusion of the basement membranes of epithelial and endothelial cells. Both of these cells are specialised in structure and function. The glomerular capillary endothelial cells contain pores (fenestrae) which allow access of circulating molecules to the underlying GBM. On the outer side of the GBM, glomerular epithelial cells (podocytes) put out multiple long foot processes which interdigitate with those of adjacent epithelial cells. These are non-dividing cells whose integrity is critical to the structure and function of the glomerulus. The death of a podocyte may lead to adhesion of the underlying GBM to Bowman's capsule, followed by the formation of a focal glomerular scar. The normal filtration barrier (see Fig. 14.1E) requires integrity of the junctions between the epithelial cells, the epithelial slit diaphragm apparatus, as well as the GBM itself, and these structures are responsible for the size limit to glomerular filtration. The filtration barrier at the glomerulus is normally almost absolute to proteins the size of albumin (67 kDa) or larger, with those of 20 kDa or smaller able to filter freely. Between these sizes there is a gradient of clearance, the behaviour of individual molecules being influenced by their shape and charge. Anionic (negatively charged) proteins are relatively less freely filtered than cationic proteins. Little lipid is filtered.
Mesangial cells lie in the central region of the glomerulus. They have similarities to vascular smooth muscle cells (e.g. contractility), but also some macrophage-like properties. In health, bone marrow-derived macrophages are occasionally found in glomeruli and in the interstitium.
Tubular cells are polarised, with a brush border (proximal tubular cells) and specialised functions at both their basal and their apical surfaces. Regionally, in the proximal convoluted tubule (PCT), thick ascending limb of the loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD) they serve distinct functions, and carry a specific complement of transporter, channel and receptor molecules (see Fig. 9.3, p. 274). Interstitial cells between tubules are less well understood. Fibroblast-like cells in the cortex are capable of producing erythropoietin in response to hypoxia. In the medulla, lipid-laden interstitial cells are believed to be important in prostaglandin production.
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Figure 14.1 Functional anatomy of the kidney. A Anatomical relationships of the kidney. B A single nephron. For the functions of different segments, see Figure 9.3, page 274. C Histology of a normal glomerulus. D Schematic cross-section of a glomerulus showing five capillary loops, to illustrate structure and show cell types. E Electron micrograph of the filtration barrier. (GBM = glomerular basement membrane)
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Figure 14.2 Endoscopic views of the upper and lower urinary tract.
COLLECTING SYSTEM AND LOWER URINARY TRACT
This part of the urinary system is illustrated in Figure 14.2. It is subject to a variety of congenital anomalies, as outlined on page 608.
CONTINENCE MECHANISMS
Continence is dependent on the anatomical structures shown in Figure 14.2 and also on neurological and muscle (sphincter and detrusor) function. Parasympathetic nerves arising from S2-4 supply the detrusor muscle. These cholinergic nerves stimulate detrusor contraction, resulting in micturition. Sympathetic nerves arising from T10-L2 relay in the pelvic ganglia before reaching the detrusor and bladder neck. Stimulation of these noradrenergic nerves produces detrusor relaxation (via ß-adrenoceptors) and contraction of the bladder neck (via a-adrenoceptors). This assists urine storage and continence during bladder filling. The distal sphincter mechanism is innervated from the sacral segments S2-4 by somatic motor fibres which reach the sphincter either by the pelvic plexus or via the pudendal nerves.
Afferent sensory impulses pass to the cerebral cortex which suppresses detrusor contractions. Their main function is to inhibit micturition until it is appropriate.
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page 581


Figure 14.3 Normal micturition cycle.
The micturition cycle
Storage (filling) phase
Due to the high compliance of the detrusor muscle the bladder fills steadily without a rise in intravesical pressure. As bladder volume increases, stretch receptors in its wall cause reflex bladder relaxation and increased sphincter tone. At approximately 75% bladder capacity there is a desire to void. Voluntary control is now exerted over the desire to void, which disappears temporarily. Compliance of the detrusor allows further increase in capacity until the next desire to void. Just how often this desire needs to be inhibited depends on many factors, not the least of which is finding a suitable place in which to void.
Voiding (micturition) phase
The act of micturition is initiated first by voluntary and then by reflex relaxation of the pelvic floor and distal sphincter mechanism, followed by reflex detrusor contraction. These actions are coordinated by the pontine micturition centre. Intravesical pressure remains greater than urethral pressure until the bladder is empty. Disorders of micturition may therefore be structural or neurogenic.
The normal micturition cycle is illustrated in Figure 14.3.
INVESTIGATION OF RENAL AND URINARY TRACT DISEASE
TESTS OF FUNCTION


Figure 14.4 Factors affecting blood levels of urea and creatinine. Factors affecting intake and production are shown to the left ('in'); those affecting excretion are shown to the right ('out'). Creatinine intake is omitted here as dietary creatinine (from meat) only rarely influences blood levels.
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page 582
14.1 GLOMERULAR FILTRATION RATE (GFR)
The GFR is the rate at which fluid passes into nephrons after filtration at the glomerulus, and is a measure of the overall function of the kidney. Its normal range depends on the size of an individual, so GFR is often reported after normalisation for surface area-typically 1.73 m2. About 95% of the normal population have values within these limits. Average values for men are 12% higher than those for women:


Measuring clearance to estimate GFR
Most solutes are reabsorbed from or additionally secreted into renal tubules, so simple measurements of their concentration in urine or blood do not give reliable information about glomerular filtration. Inulin is an example of a substance that is freely filtered and not altered by tubular function, but measurements of clearance are difficult. Disappearance of trace amounts of radio-labelled ethylenediamine-tetraacetic acid (EDTA) from the blood can be measured more simply
Creatinine clearance (CrCl) is relatively simple to measure, as no injections are required; measurements of serum concentration and the amount of creatinine in a 24-hour urine collection are needed. It is calculated as follows (care with units is required:
However, CrCI exaggerates GFR when renal function is poor and may be affected by drugs that alter tubular creatinine secretion (e.g. trimethoprim, cimetidine). Its reliability also depends on accurate urine collection
Equations
Equations have been shown to be a reliable and consistent way of assessing GFR from serum creatinine alone. The Cockcroft and Gault equation is widely used, and is reasonably accurate at normal to moderate renal function. However, it was designed to estimate CrCl, not GFR. Better equations have been developed for poorer levels of function (e.g. creatinine > 180 µmol/l):
The Modification of Diet in Renal Disease (MDRD) study equation is particularly well proven in 'standard' patients at varying levels of renal function but is complex; calculators are available on-line (see Further information, p. 639) or on portable electronic devices. It is unwise to expect any of these equations to perform well in unusual circumstances, such as extremes of body mass


Blood urea is a poor guide to renal function as it varies with protein intake, liver metabolic capacity and renal perfusion (see Fig. 14.4). Serum creatinine is a more reliable guide as it is produced from muscle at a constant rate and almost completely filtered at the glomerulus. As very little creatinine is secreted by tubular cells, the creatinine clearance provides a reasonable approximation of the glomerular filtration rate (see Box. 14.1). If muscle mass remains constant, changes in creatinine concentration reflect changes in GFR. However, an increase outside the normal range is typically not seen until GFR is reduced by about 50% (see Fig. 14.5), and isolated measurements of creatinine give a misleading impression of renal function in those with unusually small amounts (and occasionally in those with very large amounts) of muscle. More accurate measurement of GFR is now most easily undertaken by ascertaining the clearance of 51Cr-labelled ethylenediamine-tetraacetic acid (EDTA). This has largely replaced estimation of inulin clearance in clinical practice.


Figure 14.5 Serum creatinine and the glomerular filtration rate (GFR).
The inverse reciprocal relationship between GFR and serum creatinine is shown for a group of patients with renal disease. The red band indicates the range of values obtained. Note that some individuals have a GFR as low as 30-40 ml/min without serum creatinine rising out of the normal range.
Tests of tubular function, including concentrating ability, ability to excrete a water load and ability to excrete acid, are valuable in some circumstances.
IMAGING TECHNIQUES
Plain radiographs may show the renal outlines if perinephric fat and bowel gas shadows permit. Opaque calculi and calcification within the renal tract may also be shown.
Ultrasound
This quick, non-invasive technique is the first and often the only method required for renal imaging. It can show renal size and position, dilatation of the collecting system (suggesting obstruction, see Fig. 14.6), distinguish tumours and cysts, and show other abdominal, pelvic and retroperitoneal pathology. In addition, it can image the prostate and bladder, and estimate completeness of emptying in suspected bladder outflow obstruction. Images are often less clear in obese individuals. Ultrasonographic density of the renal cortex is increased and corticomedullary differentiation lost in chronic renal disease.
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Figure 14.6 Renal ultrasound. A Normal kidney. The normal cortex is less echo-dense (blacker) than the adjacent liver. B A simple cyst occupies the upper pole of an otherwise normal kidney. C The renal pelvis and calyces are dilated by a chronic obstruction to urinary outflow. The thinness and increased density of the remaining renal cortex indicate chronicity.
Doppler techniques are used to show blood flow and its characteristics in extrarenal and larger intrarenal vessels. The resistivity index is the ratio of peak systolic and diastolic velocities, and is influenced by the resistance to flow through small intrarenal arteries. It may be elevated in various diseases, including acute glomerulonephritis and rejection of a renal transplant. While severe renal artery stenosis causes damping of flow in intrarenal vessels, with high peak velocities, to date ultrasound has not proved to be a reliable technique for detecting renal artery stenosis.
The disadvantages of renal ultrasound are that it is operator-dependent and that the printed images convey only a fraction of the information gained by performing the investigation in real time.
Intravenous urography (IVU)


Figure 14.7 Intravenous urograms. A Nephrogram phase at 1 minute. B Collecting system at 5 minutes. C Intravenous urogram showing a later view of a normal collecting system on the patient's left, with obstruction of the right system by a transitional cell carcinoma of the upper ureter, shown as a filling defect (arrow).
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14.2 RENAL COMPLICATIONS OF RADIOLOGICAL INVESTIGATIONS
Contrast nephrotoxicity
An acute deterioration in renal function, sometimes life-threatening, commencing within 24 hrs of administration of i.v. radiographic contrast media
Risk factors
Pre-existing renal impairment
Use of high-osmolality contrast media
Diabetes mellitus-especially if treated with metformin
Myeloma
Prevention
Hydration-e.g. free oral fluids plus i.v. isotonic saline 500 ml then 250 ml/hr during procedure
Avoid nephrotoxic drugs; withhold non-steroidal anti-inflammatory drugs (NSAIDs); omit metformin for 48 hrs
Most other measures are ineffective or increase (e.g. diuretics) the risk
If the risks are high, consider alternative methods of imaging
Cholesterol atheroembolism
Typically follows days to weeks after intra-arterial investigations-see page 611


While intravenous urography has been largely replaced by ultrasound for routine renal imaging, this technique provides excellent definition of the collecting system and ureters, and remains superior to ultrasound for examining renal papillae, stones and urothelial malignancy (see Fig. 14.7). Radiographs are taken at intervals following administration of an intravenous bolus of an iodine-containing compound that is excreted by the kidney. An early image (1 minute after injection) will demonstrate the nephrogram phase of renal perfusion in patients with an adequate renal arterial supply. This is followed by contrast filling the collecting system, ureters and bladder. The disadvantages of this technique are the need for an injection, time requirement, dependence on adequate renal function for good images, and risk of exposure to contrast medium (see Box 14.2).
Pyelography
Pyelography (direct injection of contrast medium into the collecting system from above or below) offers the best views of the collecting system and upper tract, and is commonly used to identify the cause of urinary tract obstruction (see p. 590). Antegrade pyelography requires the insertion of a fine needle into the pelvicalyceal system under ultrasound or radiographic control. Contrast is injected to outline the collecting system, and particularly to localise the site of obstruction. This approach is much more difficult and hazardous in a non-obstructed kidney. In the presence of obstruction, percutaneous nephrostomy drainage can be established, and often stents can be passed through any obstruction. Retrograde pyelography can be performed by inserting catheters into the ureteric orifices at cystoscopy (see Fig. 14.8).
Renal arteriography and venography
The main indication for renal arteriography is to investigate suspected renal artery stenosis (see p. 609) or haemorrhage. In the absence of computed tomography it is also valuable for defining renal tumours. Therapeuticballoon dilatation and stenting of the renal artery may be undertaken, and bleeding vessels or arteriovenous fistulae occluded.
Computed tomography (CT)


Figure 14.8 Retrograde pyelography. The best views of the normal collecting system are shown by pyelography. A catheter has been passed into the left renal pelvis at cystoscopy. The anemone-like calyces are sharp-edged and normal. (Compare with the obstructed system shown in Figure 14.7C.)
While not routinely of greater value than ultrasound, CT is particularly useful for characterising mass lesions within the kidney (see Fig. 14.40, p. 635), or combinations of cysts with masses. It gives clearer definition of the retroperitoneal anatomy and, unlike ultrasound, is aided by increased amounts of fat.
Spiral CT is a rapid-sequence technique, with images obtained immediately following a large bolus injection of intravenous contrast media to outline vascular structures. It produces high-quality images of the main renal vessels and, when used to screen for possible renal artery stenosis in secondary hypertension, has the advantage of providing renal and adrenal images at the same time. It is also a very useful technique for demonstrating renal stones.
Magnetic resonance imaging (MRI)
MRI offers excellent resolution and distinction between different tissues. Magnetic resonance angiography (MRA) uses gadolinium-based contrast media which are non-nephrotoxic, and avoids the risk of atheroemboli. It can produce good images of main renal vessels. These techniques are likely to develop further and find an important role in non-invasive screening for renal artery stenosis. The relative places of spiral CT and MRA for this condition have yet to be defined.
SPECIAL TESTS
Radionuclide studies
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Figure 14.9 DMSA isotope renogram. A posterior view is shown of a normal left kidney and a small right kidney (with evidence of cortical scarring at upper and lower poles) which contributes only 39% of total renal function.
These studies require the injection of gamma ray-emitting radiopharmaceuticals which are taken up and excreted by the kidney, a process which can be monitored by an external gamma camera. In this way, the function of individual kidneys can be assessed.
Diethylenetriamine-pentaacetic acid labelled with technetium (99mTc-DTPA) is excreted by glomerular filtration. Following injection of DTPA, computer analysis of uptake and excretion can be used to provide information regarding the arterial perfusion of each kidney. In renal artery stenosis, transit time is prolonged, peak activity delayed and excretion reduced. In less severe but still significant stenosis, a single dose of an angiotensin-converting enzyme (ACE) inhibitor ('captopril renography') can, by inhibiting the compensatory efferent glomerular arteriolar constriction induced by angiotensin II, induce these changes in a kidney that previously perfused normally, although this is not a reliable enough technique for screening. In patients with significant obstruction of the outflow tract, persistence of the nuclide in the renal pelvis is seen (see Fig. 14.12, p. 591), and a loop diuretic fails to accelerate its disappearance.
Dimercaptosuccinic acid labelled with technetium (99mTc-DMSA) is filtered by glomeruli and partially bound to proximal tubular cells. Following intravenous injection, images of the renal cortex show the shape, size and function of each kidney (see Fig. 14.9). This is a sensitive method of demonstrating early cortical scarring that is of particular value in children with vesico-ureteric reflux and pyelonephritis. It is also possible to assess the relative contribution of each kidney to total function.
Renal biopsy
Renal biopsy is used to establish the nature and extent of renal disease in order to judge the prognosis and need for treatment. The indications, contraindications and complications are given in Box 14.3. The procedure is performed with ultrasound guidance to ensure accurate needle placement into a renal pole. Radiographic screening after contrast administration or other methods may also be used. Light microscopy, electron microscopy and immunohistological assessment of the specimen may all be required.
14.3 RENAL BIOPSY
Indications
Acute renal failure that is not adequately explained
Chronic renal failure with normal-sized kidneys
Nephrotic syndrome or glomerular proteinuria in adults
Nephrotic syndrome in children that has atypical features or is not responding to treatment
Isolated haematuria with renal characteristics or associated abnormalities

Contraindications
Disordered coagulation or thrombocytopenia
Uncontrolled hypertension
Kidneys < 60% predicted size
Solitary kidney (except transplants) (relative contraindication)

Complications
Pain, usually mild
Bleeding into urine, usually minor but may produce clot colic and obstruction
Bleeding around the kidney, occasionally massive and requiring angiography with intervention, or surgery
Arteriovenous fistula, rarely clinically significant


pages 578 - 585


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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > MAJOR MANIFESTATIONS OF RENAL AND URINARY TRACT DISEASE
MAJOR MANIFESTATIONS OF RENAL AND URINARY TRACT DISEASE
GENERAL MANIFESTATIONS OF RENAL DISEASE
The broad categories of renal and urinary tract disease, and the typical manifestations that they may cause, are indicated in Figure 14.10. Symptoms related directly to the kidneys are uncommon in intrinsic or pre-renal disorders, and identification of such diseases is further complicated by the fact that loss of renal function is, with some exceptions, only recognised clinically at a late stage. Exceptions include the polyuria or sodium-wasting of some tubular disorders. More commonly, sodium retention and fluid imbalance lead to hypertension and oedema.
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Figure 14.10 Manifestations of renal and urinary tract disease.
While non-inflammatory and subacute inflammatory/proliferative glomerular disorders may present with substantial proteinuria resulting in nephrotic syndrome (see p. 589), inflammatory glomerular disorders more typically cause haematuria in association with early signs of disturbed renal function, such as hypertension. If progressive, obvious signs of impaired excretion of water and solutes develop. The onset of these features in close succession has been described as the nephritic syndrome (see Box 14.6), but in pure form this condition is seen rarely, except in countries where post-infectious glomerulonephritis is common. Mixed inflammatory and nephrotic features are more common. It is important to recognise such disease, especially if renal impairment is progressing, as the inflammatory group includes some of the most treatable renal disorders.
Hypertension is a very common feature of renal parenchymal and vascular disease. Renal mechanisms are also likely to be important in essential hypertension. Most inherited causes of disordered blood pressure have been attributed to altered salt and water handling by the kidney. Hypertension is an early feature of glomerular disorders. In interstitial disorders, sodium loss (through reduced reabsorption from glomerular filtrate) may lead to hypotension. However, as GFR declines, hypertension becomes an increasingly common feature, regardless of the aetiology of the renal disease. When renal function is replaced by dialysis, control of hypertension often becomes easier as salt and volume balance are controlled. Obsessional attention to fluid balance in haemodialysis patients may reduce or remove the need for hypotensive drugs. Control of hypertension is very important in those with renal impairment because of its close relationship with further decline of renal function (see p. 391).
URINARY ABNORMALITIES
DISORDERS OF URINE VOLUME
Urine volume gives a poor guide to renal function unless it is inappropriate to the circumstances. On a normal diet, between 300 and 500 ml/day are needed to excrete solutes at maximum concentration. Complete anuria suggests either an acute vascular event or total urinary obstruction; even in the most severe intrinsic renal disorders some urine is usually still produced. Polyuria, which refers to the production of an excess volume of urine (> 3 l/day), may have a number of causes (see Box 14.4). Oliguria is discussed on pages 594-595.
14.4 CAUSES OF POLYURIA
Excess fluid intake
Osmotic, e.g. hyperglycaemia
Cranial diabetes insipidus (loss of antidiuretic hormone-ADH)-see page 744
Nephrogenic diabetes insipidus (tubular dysfunction)
Genetic tubular cell defects: ADH receptor, aquaporin mutations
Drugs/toxins: lithium, diuretics, hypercalcaemia
Interstitial renal disease (see p. 618)


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HAEMATURIA
Haematuria may indicate bleeding from anywhere in the renal tract (see Fig. 14.11). Dipstick tests are very sensitive and can identify all significant bleeding. Microscopy shows that normal individuals have occasional red cells in the urine, and positive tests may occur during menstruation, but persistent haematuria requires explanation, particularly in older age groups or others at risk of carcinoma of the bladder or other malignancy (see EBM panel). Macroscopic (visible) haematuria is particularly likely to be caused by tumours (see pp. 634-636). Urine microscopy (see p. 577) can be valuable in establishing the cause of bleeding. The presence of white blood cells and organisms may suggest infection; the presence of red cell casts indicates glomerular bleeding; a high proportion of dysmorphic erythrocytes (best seen by phase-contrast microscopy) likewise supports glomerular bleeding. In the absence of evidence of intrinsic renal disease, however, urological tract investigations should come first, at least in patients over 35 years of age.


Figure 14.11 Causes of haematuria. See Box 14.5 for other causes of red or dark urine.
EBM
ISOLATED HAEMATURIA-malignancy as an important cause
'In a large series of patients investigated for haematuria, 13% had urinary tract infections, 12% had bladder cancer and 2% had unsuspected renal stones. No basis for it was found in 61%. The likelihood of renal disease is low unless there are associated features, notably proteinuria, raised serum creatinine or hypertension.'
Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1930 patients with hematuria to evaluate current diagnostic practice. J Urology 2000; 163:524-527.
Further information: www.sign.ac.uk www.edren.org

Glomerular bleeding implies that the GBM is fractured. It may be seen physiologically following very strenuous exertion. Other causes of red or dark urine may sometimes be confused with haematuria (see Box 14.5). If haematuria occurs with pointers to renal disease, further investigations should be directed towards looking for inflammatory renal disease, usually including renal biopsy. As noted, haematuria is an important feature of patients with the nephritic syndrome (see Box 14.6).
Isolated microscopic haematuria
14.5 CAUSES OF RED OR DARK URINE
Haematuria
Haemoglobinuria: red urine, stick test for blood positive, but no red cells on microscopy
Myoglobinuria: in rhabdomyolysis. Very dark or black urine. Stick test for blood positive, but no red cells on microscopy
Food dyes: beetroot (anthocyanins)
Drugs: phenolphthalein (pink when alkaline), senna and other anthraquinones (orange), rifampicin (orange), levodopa (darkens on standing)
Porphyria (urine turns dark on standing; see p. 325)
Alkaptonuria


14.6 NEPHRITIC SYNDROME
Haematuria (brown urine)
Oedema and generalised fluid retention
Hypertension
Oliguria


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Where there are no features of significant renal disease (no hypertension, normal renal function, insignificant amounts of protein in the urine) and malignancy has been excluded, patients with isolated microscopic haematuria may be managed by observation alone. Although this scenario occasionally gives warning of significant renal disease (e.g. Alport's syndrome, IgA nephropathy), it is commonly caused by the usually benign condition of thin GBM disease (see p. 612), insignificant vascular malformations, renal cysts or renal stones. In 'loin pain-haematuria' syndrome, benign glomerular bleeding is associated with loin pain. Recurrent episodes of gross haematuria in association with respiratory infections are characteristic of IgA nephropathy (see p. 616).
PROTEINURIA
Patients are usually unaware of proteinuria, although it may make urine froth easily. Moderate amounts of low molecular weight protein are normally filtered at the glomerulus. These proteins are normally reabsorbed by tubular cells so that less than 150 mg/day should appear in the urine. Low molecular weight proteins appearing in the urine in larger quantities than this point to failure of reabsorption by damaged tubular cells, i.e. tubular proteinuria. This can be demonstrated by analysis of the size of excreted proteins or by specific assays for such proteins (e.g. ß2-microglobulin, molecular weight 12 kDa). The amounts of such protein rarely exceed 1.5-2 g/24 hrs, and proteinuria greater than this almost always indicates significant glomerular disease.
Glomerular lesions allow filtration of larger serum proteins. The presence of albumin in the urine is a sure sign of glomerular abnormality. Albumin is the dominant serum protein, with a molecular weight of 67 kDa. Assays for this protein can identify the very early stages of glomerular disease in disorders with a predictably progressive course, such as diabetic nephropathy.
Persistent microalbuminuria (below amounts detectable by dipstick testing) has also been associated with an increased risk of atherosclerosis and other diseases; neither the mechanism of proteinuria nor an explanation of these associations has yet been found.
14.7 PROTEINURIA
Excretion rate Protein/creatinine (mg/mmol)* Significance
< 0.15 g/24 hrs < 15 Normal
0.3-0.5 g/24 hrs 15-50 Stick tests positive
0.5-2 g/24 hrs 50-200 Source equivocal
> 2.5 g/24 hrs > 300 Glomerular disease likely
> 3.5 g/24 hrs > 400 Nephrotic range: always glomerular

* [Urine protein] (mg/l)/[urine creatinine] (mmol/l).
Relatively minor leakage of albumin into the urine may also occur transiently after vigorous exercise, during fever, in heart failure, and in some other disease states, accounting for some positive stick tests in these circumstances. Such proteinuria should not reach nephrotic levels (see Box 14.7), and tests should be repeated once the stimulus is no longer present. Occasionally, proteinuria occurs only during the day, and the first morning sample is negative. In the absence of other signs of renal disease, such 'orthostatic proteinuria' is usually regarded as benign.
Patients with a clone of B lymphocytes secreting free immunoglobulin light chains (molecular weight 25 kDa) filter these freely into the urine, and Bence Jones protein can then be identified in fresh urine samples. This may occur in amyloidosis (see p. 328) and other plasma cell dyscrasias, but is particularly important as a marker for myeloma (see p. 943). Some light chains are toxic to tubular cells and contribute to the damage seen in myeloma. Bence Jones protein is poorly identified by stick tests for urinary protein; specific tests (e.g. immunoelectrophoresis) must be performed. The sulphosalicylic acid precipitation test is positive in Bence Jones proteinuria but is less sensitive.
Twenty-four-hour collections of urine are arduous and often inaccurate. Use of the protein/creatinine ratio in single samples makes allowance for the variable degree of urinary dilution. For an individual with an average muscle mass and normal rate of creatinine generation, a ratio of 120 (derived from [urine protein] in mg/1 divided by the [urine creatinine] in mmol/1) corresponds to a protein excretion rate of approximately 1 g/24 hrs, and a ratio of 400 to 3.5 g/24 hrs. Regardless of absolute muscle mass, changes in this ratio can give valuable information about the progression of renal disease (see Boxes 14.7 and 14.8).
In many types of renal disease, the severity of proteinuria is a marker for an increased risk of progressive loss of renal function, and direct toxicity has been suggested. The evidence for this is mostly circumstantial, but treatments that are effective at lowering the risk of progression (e.g. ACE inhibitors in diabetic nephropathy) also reduce proteinuria.
14.8 ALBUMIN EXCRETION: ALTERNATIVE WAYS OF EXPRESSING THE NORMAL RANGE
Sample Normal value
24-hr urine collection < 30 mg/24 hrs
Timed sample from ambulant patient < 20µg/min
Timed overnight sample or from recumbent patient < 10µg/min
Albumin/creatinine ratio on a random urine sample < 2.5 mg/mmol (male)
< 3.5 mg/mmol (female)


Note A measurement of > 300 mg/24 hrs (200µg/min) represents frank proteinuria.
Isolated proteinuria
Low levels of proteinuria without other evidence of renal disease may be managed by observation alone, but are a marker for later development of hypertension and overt renal disease. Nephrotic levels of proteinuria, or lesser levels in the presence of haematuria, hypertension or renal impairment, are usually an indication for renal biopsy.
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Nephrotic syndrome
When substantial amounts of protein are lost in the urine, a series of secondary phenomena occur. It is these that constitute the nephrotic syndrome, although they begin to occur at levels of proteinuria lower than 'nephrotic range' (3.5 g/24 hrs). One formal definition of the nephrotic syndrome requires a serum albumin < 30 g/l, evidence of fluid retention or oedema, and more than 3.5 g of proteinuria/day. The diseases that cause nephrotic syndrome always affect the glomerulus (see Box 14.9) and tend to be non-inflammatory, or subacute examples of inflammatory glomerulonephritis.
There are important age-related differences in the incidence of different causes. In neonates congenital aetiologies are most common. Minimal change nephropathy is the dominant diagnosis in older children in Caucasian races; focal and segmental glomerulosclerosis (FSGS) is common in black races. In later life there is a progressive increase in the incidence of membranous nephropathy and FSGS. Diabetes mellitus and amyloidosis rarely cause nephrotic syndrome in childhood.
14.9 COMMON CAUSES OF NEPHROTIC SYNDROME
Non-inflammatory glomerulonephritis
Minimal change nephropathy
Focal and segmental glomerulosclerosis (FSGS)
Membranous nephropathy
Proliferative/inflammatory glomerulonephritis
Mesangiocapillary glomerulonephritis (MCGN)
Systemic lupus erythematosus (SLE) (with a variety of histopathological types)
Other 'subacute' proliferative nephritis
Systemic diseases
Diabetic nephropathy
Amyloidosis


14.10 CONSEQUENCES AND COMPLICATIONS OF NEPHROTIC SYNDROME
Oedema
Caused by avid sodium retention and hypoalbuminaemia
Hypercoagulability
Presumed relative loss of inhibitors of coagulation and excessive production of coagulation factors
Venous thromboembolism is common and sometimes fatal
Hypercholesterolaemia
High rate of arterial occlusions and disease
Infection
Especially by pneumococci
Associated with hypogammaglobulinaemia


The consequences and complications of the nephrotic syndrome are listed in Box 14.10. Oedema accumulates predominantly in the lower limbs in adults, extending to the genitalia and lower abdomen as it becomes more severe. In the morning, the upper limbs and face may be more affected. In children, ascites occurs early and oedema is often seen only in the face. Blood volume may be normal, reduced or increased. Avid renal sodium retention is an early and universal feature.
Management of nephrotic syndrome has four elements:
Establish the cause.
Treat the cause if possible.
Treat the symptoms.
Prevent complications.

In children with nephrotic syndrome, initial management includes administration of high-dose corticosteroids. In older patients, and in children where this therapy is unsuccessful, a renal biopsy is essential unless there is strong evidence for a specific aetiology (e.g. a long history of diabetes, with other microvascular complications and a demonstrated progression from microalbuminuria, and with hypertension but no haematuria).
Symptomatic oedema is controlled by diuretics and a low-sodium diet (no added salt). In severe nephrotic syndrome very large doses of combinations of diuretic acting on different parts of the nephron (e.g. loop diuretic plus thiazide plus amiloride) may be required. In occasional patients with evidence of hypovolaemia, intravenous salt-poor albumin infusions may help to establish a diuresis. Over-diuresis risks secondary impairment of renal function through hypovolaemia. Venous thromboembolism is guarded against by anticoagulation and there is a case for routine anticoagulation in all patients with chronic or severe nephrotic syndrome. Hypercholesterolaemia is common and treated with lipid-lowering drugs (e.g. HMG CoA reductase inhibitors, see p. 311). However, controlled trials have not been reported for this patient group. The risk of infection with pneumococci is especially high in children, who should be offered immunisation.
OEDEMA
APPROACH TO THE PATIENT WITH OEDEMA
Oedema may form locally or generally. There are three mechanisms, each of which acts on the 'Starling forces' that maintain tissue fluid volumes. Box 14.11 lists these mechanisms and gives major examples of each. In developed countries the most common causes are local venous problems and heart failure, but it is important to differentiate the others.
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14.11 OEDEMA
Lowered oncotic pressure of blood
Characterised by low serum albumin (a representative of total serum proteins and the major serum protein) because of reduced synthesis or increased loss. Many of these conditions are also associated with avid sodium retention by the kidney. All cause generalised oedema that is worse in dependent regions:
Liver failure-particular tendency to form ascites
Nephrotic syndrome-urine testing will be strongly positive for protein
Malnutrition or malabsorption

Increased capillary permeability
Leakage of proteins into the interstitium reduces the osmotic pressure gradient that draws fluid back into the lymphatics and blood:
Locally with infection or inflammation
Systemically in severe sepsis-probably related to circulating cytokines
Drug-related-e.g. calcium channel blockers

Increased hydrostatic pressure
Increased hydrostatic pressure in veins or lymphatics reduces fluid return to the circulation. Venous pressure is generally high in heart failure or with volume (or sodium) overload:
Venous-high venous pressure or obstruction
Deep venous thrombosis or venous insufficiency-causes local oedema
Other local causes of obstruction-pregnancy, tumour
Heart failure-common cause of generalised oedema
Renal failure with intravascular volume expansion

Lymphatic-lymphatic obstruction
Termed lymphoedema when chronic. Characteristically non-pitting; always localised:
Infection-filariasis, lymphogranuloma venereum (see pp. 73 and 104)
Malignancy
Radiation injury
Congenital abnormality


It is easy to mistake the first signs of generalised oedema for a local problem. Firstly, substantial volumes (litres) of extracellular fluid (ECF) may accumulate without any clinical signs. In adults dependent regions or immobile limbs are usually the first site of oedema formation. Ankle-swelling is characteristic, but oedema develops over the sacrum in bed-bound patients. It rises higher up the lower limbs with increasing severity, to affect the genitalia and abdomen. Ascites is common and often an earlier feature in children or young adults, and in liver disease. Pleural effusions are common and can be a feature of any cause of generalised oedema. Facial oedema on waking is common in adults with low oncotic pressure oedema. Like ascites, it is a more common feature of oedema in young patients.
Lower limb oedema is common in morbid obesity. Although venous obstruction may often be a problem, it may also be multifactorial-for example, right heart failure caused by sleep apnoea.
Diagnosis
The cause of oedema is usually apparent quite quickly from the history and from examination of the cardiovascular and gastrointestinal systems, followed by testing the urine for protein. A serum albumin level is also relevant. Where ascites or pleural effusions in isolation are causing diagnostic difficulty, aspiration of fluid with measurement of protein and glucose, and microscopy for cells, will usually give the answer (see pleural effusion, p. 501).
Management
Where a specific cause is apparent (e.g. venous thrombosis) this should be treated. Diuretics are commonly used, but also commonly abused, for oedema. Where there is sodium retention and generalised oedema, restriction of sodium (and sometimes fluid) intake is rational, along with diuretic treatment. However, in oedema caused by venous or lymphatic obstruction or by inflammation, diuretics are likely to be hazardous, as they will cause hypovolaemia. Local treatments, such as the use of compression either continuously (e.g. compression stockings) or intermittently (with a mechanical device), can be useful in these circumstances.
Mild fluid retention will respond to a thiazide or to a low dose of a loop diuretic such as furosemide (frusemide) or bumetanide. Withdrawing therapy when the cause has resolved can lead to transient 'rebound' oedema. In nephrotic syndrome, renal failure and severe cardiac failure, very large doses of diuretics, sometimes in combination, may be required to achieve a negative sodium and fluid balance.
OBSTRUCTION OF THE URINARY TRACT
UPPER TRACT OBSTRUCTION
Obstruction to the upper renal tract may be due to extrinsic, intrinsic or intraluminal pathology in the renal pelvis or ureter. Stones within the renal pelvis (see p. 632) and congenital abnormality of the pelvi-ureteric junction (PUJ) are the main causes of obstruction. More rarely, a sloughed renal papilla, blood clot, tumour (see pp. 635-636, and Fig. 14.7, p. 583), retroperitoneal fibrosis or chronic infection may obstruct either kidney or ureter (see Fig. 14.12).
Renal stones
Renal stones are described on page 632.
Pelvi-ureteric junction obstruction (idiopathic hydronephrosis)
This results from a functional obstruction at the junction of the ureter and renal pelvis despite normal muscle cells on electron microscopy. The aetiology is obscure. The abnormality is likely to be congenital and is often bilateral. It can be seen in very young children, but gross hydronephrosis may present at any age.
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Figure 14.12 Urinary tract obstruction. Some common causes and their locations. Compare with images in Figure 14.2.
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The common presentation is ill-defined renal pain or ache exacerbated by drinking large volumes of liquid. Rarely, it is asymptomatic. Diagnosis is suspected after ultrasound or IVU and confirmed with a diuretic renogram. Treatment is surgical excision of the PUJ and reanastomosis (pyeloplasty). Less invasive alternatives have been developed, including balloon dilatation and endoscopic pyelotomy. These are simpler but have not been evaluated over very long periods of follow-up.
Retroperitoneal fibrosis
Fibrosis of the retroperitoneal connective tissues may encircle and compress the ureter(s), causing obstruction. This fibrosis is most commonly idiopathic, but can represent a reaction to infection, radiation or blood (aortic aneurysm), or be caused by cancer or a drug reaction. Patients usually present with ill-defined symptoms of ureteric obstruction. Typically, there is an acute phase response (high C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)). IVU or CT shows ureteric obstruction with medial deviation of the ureters. Idiopathic retroperitoneal fibrosis responds well to steroids; failure to respond indicates the need for surgery to exclude malignancy and relieve obstruction.
Other causes
The ureter may be obstructed by opening into a ureterocele within the bladder (see Fig. 14.12). Primary megaureter may be obstructive or non-obstructive at the point where the ureter enters the bladder wall. Narrowing of the ureter and reimplantation may be necessary. In many parts of the developing world tuberculosis or schistosomiasis is also a common cause of ureteric stricture and obstruction (see pp. 532 and 76). Often patients present in such an advanced state of disease that surgical treatment is not feasible. Both infections require specific drug treatment. When the ureters are involved and obstructed, a variety of reconstructive surgical procedures may be used to conserve renal function and correct obstruction and/or reflux.
LOWER TRACT OBSTRUCTION
In older males the most common cause of obstruction of the lower renal tract is benign hyperplasia of the prostate (see p. 636); in younger males the obstruction may be due to bladder neck dyssynergia. This can be managed by a-adrenoceptor antagonists but endoscopic surgical division of the bladder neck may be preferable as long as the risk of retrograde ejaculation and therefore infertility is not of concern to the patient. Carcinoma of the prostate (see p. 638) is a less frequent but important cause of lower tract obstruction.
Urethral stricture should be considered if there is a history of urethral infection, instrumentation (including catheterisation) or trauma. The flow pattern is distinctive (see Fig. 14.13). Treatment is by stretching, cutting or urethroplasty. Obstruction may also be the result of a tight phimosis, meatal stricture or of tight urethral valves.
In neurological disorders such as spinal injury, spina bifida and multiple sclerosis, the distal sphincter may fail to relax, resulting in obstruction. Specialised urodynamic investigation is required to make an accurate diagnosis. Treatment may require endoscopic sphincterotomy.
INCONTINENCE
Disorders of micturition may relate either to problems in urine storage that result in incontinence (e.g. stress incontinence, urge incontinence or continual incontinence associated with fistulae) or to problems in voiding with poor urine flow and poor bladder emptying resulting in either acute retention or chronic retention with overflow incontinence (see Fig. 14.13). Abnormalities of function of the lower urinary tract can be confusing because different pathologies can produce similar symptoms. Incontinence is defined as involuntary loss of urine sufficient to cause a social or hygiene problem. It may occur transiently during an acute illness or hospitalisation, especially in older people.
STRESS INCONTINENCE
With stress incontinence leakage occurs because passive bladder pressure exceeds the urethral pressure, either because of poor pelvic floor support or because of a weak urethral sphincter. Most often there is an element of both. This is very common in women and most often seen following childbirth. It is only rarely seen in men and then usually following surgery to the prostate. Urine leaks when abdominal pressure rises, e.g. when coughing or laughing. In women, perineal inspection may reveal leakage of urine when the patient coughs, and sometimes also a prolapse. Females in particular respond well to physiotherapy but if incontinence is persistent and troublesome surgical treatment is indicated.
URGE INCONTINENCE
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Figure 14.13 Urodynamic abnormalities in patients with urinary incontinence. See Figure 14.3, page 581 for normal micturition cycle. (BPH = benign prostatic hyperplasia)
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In urge incontinence leakage usually occurs because of detrusor over-activity producing an increased bladder pressure which overcomes the urethral sphincter (motor urgency). Urgency may also be driven by a hypersensitive bladder (sensory urgency) resulting from urinary tract infection (UTI) or bladder stone. In the latter circumstances incontinence is less common. The incidence of urge incontinence in women increases with age, occurring in 15% of women aged over 65 years and around 50% of those requiring nursing home care. It is also seen in men with lower urinary tract obstruction and most often remits after the obstruction is relieved (see p. 637). In such patients the diagnosis is often made on the basis of symptoms and the exclusion of urinary retention by bladder ultrasound; confirmation requires urodynamic testing (see Fig. 14.13). The mainstay of treatment is bladder retraining and anticholinergic medication. Surgery is restricted to patients who have severe day-time incontinence despite such treatment.
CONTINUAL INCONTINENCE
This suggests the presence of a fistula, usually between the bladder and vagina (vesicovaginal) or the ureter and vagina (ureterovaginal). This is most common following gynaecological surgery but is also seen in patients with gynaecological malignancy or following radiotherapy. In parts of the world where obstetric services are scarce prolonged obstructed labour can be a common cause of vesicovaginal fistulae. Continual incontinence may also be seen in infants with congenital ectopic ureters. Occasionally, stress incontinence is so severe that the patient leaks continuously. Diagnosis is confirmed by inspection of the perineum and by IVU. Treatment is surgical.
POOR BLADDER EMPTYING, ACUTE RETENTION, CHRONIC RETENTION, OVERFLOW INCONTINENCE
This group of conditions is most commonly seen in males and associated with benign prostatic hyperplasia or bladder neck obstruction (see p. 636), but may occur in either sex as a result of a failure of the detrusor muscle (atonic bladder). The latter state may be idiopathic but more commonly is the result of damage to the pelvic nerves either from surgery (commonly hysterectomy or rectal excision), trauma or infection or from compression of the cauda equina from disc prolapse, trauma or tumour. Incomplete bladder emptying can be identified by ultrasound, which reveals a significant post-micturition volume (> 100 ml). Outlet obstruction necessitates cystoscopy in most cases. Urodynamic testing can help clarify the nature of a neurological problem.
POST-MICTURITION DRIBBLE
ISSUES IN OLDER PEOPLE
INCONTINENCE
Urinary incontinence affects 15% of women and 10% of men aged over 65 years.
It may be transient due to an acute confusional state, urinary infection, medication (such as diuretics), faecal impaction or restricted mobility, and these should be treated before embarking on further specific investigation.
Established incontinence in old age is most commonly due to detrusor over-activity which may be caused by damage to central inhibitory centres or local detrusor muscle abnormalities.
Poor manual dexterity or cognitive impairment may necessitate the help of a carer to assist with intermittent catheterisation.


This is very common in men, even in the relatively young. It is due to a small amount of urine becoming trapped in the U-bend of the bulbar urethra, which leaks out when the patient moves. It is more pronounced if associated with a urethral diverticulum or urethral stricture.
NEUROLOGICAL CAUSES
Neurological disease resulting in abnormal bladder function is almost always associated with obvious neurological signs; these are described on page 1158.
RENAL FAILURE
This term is used primarily to denote failure of the excretory function of the kidneys, leading to retention of nitrogenous waste products of metabolism. Various other aspects of renal function may fail at the same time, including the regulation of fluid and electrolyte status and the endocrine function of the kidney. A wide range of clinical manifestations may therefore occur. The most fundamental categorisation of renal failure is into acute or chronic renal failure.
ACUTE RENAL FAILURE
Acute renal failure (ARF) refers to a sudden and usually reversible loss of renal function, which develops over a period of days or weeks. An increase in plasma creatinine concentration to > 200 µmol/l is often used as the biochemical definition. A reduction in urine volume occurs usually, but not always. There are many possible causes (see Fig. 14.14), and it is frequently multifactorial. The clinical picture is often dominated by the underlying condition. If the cause cannot be rapidly corrected and renal function restored, temporary renal replacement therapy may be required (see p. 605). Many of the underlying disorders giving rise to ARF are complex and carry a high mortality but, if the patient survives, normal or nearly normal renal function usually returns. The most common scenarios relate to haemodynamic disturbances, often interacting with exposure to infection and toxins, particularly drugs. When this is not immediately likely, it is important to remember other important disorders that may lead to rapid loss of renal function (see Box 14.12).
A typical biochemistry profile in a patient with ARF is shown in Figure 14.15.
REVERSIBLE PRE-RENAL ACUTE RENAL FAILURE
Pathogenesis
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The kidney can regulate its own blood flow and GFR over a wide range of perfusion pressures. When the perfusion pressure falls, as in hypovolaemia, shock, heart failure or narrowing of the renal arteries, the resistance vessels in the kidney dilate to facilitate flow. This is partly mechanical, due to decreased stretch of the vessel walls, and partly neurohumoral. Vasodilator prostaglandins are important, and this mechanism is markedly impaired by NSAIDs (see p. 627). If autoregulation of blood flow fails, the GFR can still be maintained by means of selective constriction of the post-glomerular (efferent) arteriole. This is mediated through the release of renin and generation of angiotensin II, which preferentially constricts this vessel. ACE inhibitors interfere with this response.
More severe or prolonged under-perfusion of the kidney may lead to failure of these compensatory mechanisms. Blood flow and GFR decline. The renal tubules are intact, and become hyperfunctional-i.e. tubular reabsorption of sodium and water is increased, partly through physical factors and partly through the influence of angiotensins, aldosterone and vasopressin. This leads to the formation of a low volume of urine which is concentrated (high osmolality) but low in sodium (see Box 14.13).
Clinical features


Figure 14.14 Causes of acute renal failure.


Figure 14.15 Typical biochemistry profile in a patient with acute renal failure.
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14.12 RAPID LOSS OF RENAL FUNCTION: IMPORTANT CAUSES IN A HAEMODYNAMICALLY STABLE, NON-SEPTIC PATIENT
Urinary tract obstruction
Can usually be excluded by ultrasound examination
Vascular event
Major vascular occlusion. Urine usually shows minimal abnormalities, or there may be haematuria if infarction is occurring. Remember effect of ACE inhibitors in critical renal artery stenosis. Small-vessel diseases (see p. 610), notably malignant hypertension and haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura, may also be responsible
Rapidly progressive glomerulonephritis (RPGN)
Aggressive glomerular inflammation, usually with crescent formation, requiring urgent diagnosis and treatment. Typically, there is significant haematuria and proteinuria (usually = 3+ dipstick tests for both, often with red cell casts or 'glomerular' red cells) and sometimes associated systemic features of the causative condition (e.g. systemic vasculitis, SLE). Kidneys are normal size. At a late stage, oliguria is usual. See pages 597-598
Acute interstitial nephritis
Acute inflammation within the tubulo-interstitium. Most commonly an allergic reaction to a drug. Characterised by small amounts of blood and protein in urine, although leucocyturia is common. Kidneys are normal size. Requires cessation of drug and often prednisolone treatment. See page 617
Drugs
Damage results from haemodynamic effects (e.g. NSAIDs, ACE inhibitors), acute allergic interstitial nephritis or direct toxicity to the tubule (e.g. aminoglycosides)


14.13 DIAGNOSIS OF PRE-RENAL ACUTE RENAL FAILURE
A compatible history
The clinical findings
A progressive increase in blood urea and plasma creatinine
Urine osmolality > 600 mOsm/kg; urine sodium <> 10:1
The urinary findings depend on the kidneys' ability to respond to inadequate perfusion by intense conservation of sodium and water. They may therefore not be found in patients with pre-existing renal impairment or those who have received loop diuretics. Regardless of the likely aetiology of ARF, it is almost always appropriate to correct inadequate renal (and other organ) perfusion swiftly.



Figure 14.16 Septic post-operative patient with pulmonary artery catheter.
There may be a marked reduction of blood pressure and signs of poor peripheral perfusion, such as delayed capillary return. However, pre-renal ARF may occur without systemic hypotension. Postural hypotension (a fall in blood pressure of = 20/10 mmHg from lying to standing) is a valuable sign of hypovolaemia. The cause of the reduced renal perfusion may be obvious, but concealed blood loss can occur into the gastrointestinal tract, following trauma (particularly where there are fractures of the pelvis or femur) and into the pregnant uterus. Large volumes of intravascular fluid are lost into tissues after crush injuries or burns, or in severe inflammatory skin diseases or sepsis. Metabolic acidosis and hyperkalaemia are often present.
A particular form of ARF is seen in septic patients (see Fig. 14.16). The causation is multifactorial. It may in part reflect the action on the kidney of bacterial endotoxin and other mediator substances which are activated in the sepsis syndrome. Most septic patients, if they are volume-resuscitated, show vasodilatation of the systemic circulation; this leads to a relative under-filling of the arterial tree and the kidney responds as it would to absolute hypovolaemia. Measures to optimise circulatory parameters, if instituted sufficiently early, will often restore kidney function; this may involve the use of vasoconstrictor agents such as noradrenaline (norepinephrine). When it is severe or prolonged, sepsis is an important cause of established ARF with acute tubular necrosis. The combination of sepsis and NSAIDs is a potent cause of acute renal failure.
Management
The underlying cause of the ARF must be established and corrected. When hypovolaemia is present, the blood volume must be restored as rapidly as possible, by replacement with blood, plasma or isotonic saline (0.9%), depending on what has been lost. If metabolic acidosis is severe, isotonic sodium bicarbonate (e.g. 500 ml of 1.26%) may be included as part of the replacement fluid. In most cases, however, restoration of blood volume will restore kidney function and allow correction of acidosis. It is often helpful to monitor the central venous pressure or pulmonary wedge pressure as an adjunct to clinical examination in determining the rate of administration of fluid. Recent trials do not support the use of low-dose dopamine in severely ill patients at risk of ARF (see EBM panel).
As well as optimisation of volume status, patients with cardiogenic or septic shock (see p. 195) may require invasive haemodynamic monitoring to assess cardiac output and systemic vascular resistance, and the use of inotropic drugs to restore an effective blood pressure.
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EBM
ACUTE RENAL FAILURE-role of low-dose dopamine
'Dopamine at low, 'renal' doses has been used for many years in the belief that it may increase renal blood flow in critically ill patients (as it does in normal individuals) and prevent acute renal failure. There is minimal evidence for benefits from clinical trials, and suggestions that it may do harm. In an RCT including 328 patients in 23 intensive care units in Australia, dopamine 2 µg/kg/min was no different from placebo, doing neither harm nor good. There is no evidence to support the use of low-dose dopamine for prevention or modification of acute renal failure.'
ANZICS Clinical Trials Group. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet 2000; 356:2139-2143.
O'Leary MJ, Bihari DJ. Preventing renal failure in the critically ill. BMJ 2001; 322:1437-1438.


Prognosis
If treatment is given sufficiently early, renal function will usually return rapidly; in such circumstances residual renal impairment is unlikely. In some cases, however, treatment is ineffective and renal failure becomes established.
ESTABLISHED ACUTE RENAL FAILURE
Established ARF may develop following severe or prolonged under-perfusion of the kidney (pre-renal ARF). In such cases, the histological pattern of acute tubular necrosis is usually seen. Alternatively, patients may present de novo with established ARF, due to intrinsic disease of the kidney, rapidly progressive glomerulonephritis, or to obstruction of the urinary tract (see Fig. 14.14).
Acute tubular necrosis (ATN)
Acute necrosis of renal tubular cells (see Fig. 14.32, p. 618) may result from ischaemia or nephrotoxicity, caused by chemical or bacterial toxins. In practice, multiple factors are common.
Pathogenesis of acute tubular necrosis
Ischaemic tubular necrosis usually follows a period of shock, during which renal blood flow is greatly reduced. Measurements during the oliguric phase of ATN indicate that, even when the systemic circulation has been restored, renal blood flow remains at about 20% of normal. This is due to swelling of the endothelial cells of the glomeruli and peritubular capillaries, and oedema of the interstitium. Blood flow is further reduced by vasoconstrictors such as thromboxane, vasopressin, noradrenaline (norepinephrine) and angiotensin II, partly counterbalanced by the release of intrarenal vasodilator prostaglandins. Thus, in ischaemic ATN there is reduced oxygen delivery to the tubular cells, which are very active metabolically, particularly in the thick ascending limb of the loop of Henle. Their high oxygen requirement is largely driven by the active reabsorption of sodium, and even in health the renal medulla is critically balanced in terms of oxygen delivery and consumption.
The ischaemic insult causes peroxidation of cell membrane lipids, influx of calcium and cell swelling. Mitochondrial function is impaired, leading to anaerobic glycolysis and intracellular acidosis, and ultimately to lysosomal disruption, denaturation of proteins and DNA, and death of tubular cells (see Fig. 14.32, p. 618). There is loss of adhesion between tubular cells and the basement membrane, leading to shedding of cells into the tubular lumen, where they may contribute to tubular obstruction. Focal breaks in the tubular basement membrane develop; these allow tubular contents to leak into the interstitial tissue and cause interstitial oedema.
In nephrotoxic ATN a similar sequence occurs, but it is initiated by direct toxicity of the causative agent to tubular cells. Mechanisms of cell damage include the production of reactive oxygen species and peroxidation of membrane lipids, binding of toxins or drugs to target intracellular proteins to interfere with cellular respiration, and inhibition of cell protein synthesis. Examples include the aminoglycoside antibiotics, such as gentamicin, the cytotoxic agent cisplatin, and the antifungal drug amphotericin B.
Fortunately, tubular cells can regenerate and re-form the basement membrane. If the patient is supported during the regeneration phase, kidney function returns. There is often a diuretic phase where urine output increases rapidly and remains excessive for several days before returning to normal. This is due in part to loss of the medullary concentration gradient, which normally allows concentration of the urine in the collecting duct, and which depends on continued delivery of filtrate to the ascending limb of the loop of Henle and active tubular transport. Both factors are disturbed during ATN. The medullary concentration gradient is gradually 'washed out', and is not re-established until glomerular filtration and tubular function are restored. Not all patients have a diuretic phase, depending on the severity of the renal damage and the rate of recovery.
Rapidly progressive glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) is an extreme inflammatory nephritis which causes rapid loss of renal function over days to weeks. Renal biopsy shows crescent formation (see Fig. 14.30E, p. 615); indeed, 'crescentic nephritis' is another term for RPGN. It can occur in a number of diseases (see Box 14.14), some of which (e.g. vasculitis, SLE) may cause symptoms and signs in other systems, while others (e.g. anti-GBM disease) do not. Where there are other symptoms, differentiating these diseases from subacute infection (e.g. endocarditis) is very important.
Early recognition can salvage kidney function and prevent other serious consequences of underlying disease (see Box 14.14). Sometimes treatment can be commenced before the diagnosis is certain, if confirmatory tests will follow shortly.
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14.14 RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (CRESCENTIC NEPHRITIS)
Recognition
Rapid loss of renal function over days to weeks
Urine contains blood and protein
Normal or large unobstructed kidneys on ultrasound
Possible evidence of systemic illness or of disease affecting other organs (but not always)

Defining the cause
Blood tests: antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-GBM antibodies, complement immunoglobulins
Renal biopsy

Common causes
Systemic vasculitis (focal necrotising glomerulonephritis)
SLE
Goodpasture's (anti-GBM) disease
Aggressive phase of other inflammatory nephritis (e.g. IgA nephropathy, post-infectious (post-streptococcal) glomerulonephritis)

Management
Immunosuppressive treatment, e.g. cyclophosphamide and prednisolone for most causes
Supportive treatment, e.g. dialysis when indicated


Other causes of established ARF
Established ARF may also develop in conditions affecting the intrarenal arteries and arterioles, such as vasculitis, accelerated hypertension and disseminated intravascular coagulation. Acute allergic interstitial nephritis (see p. 617), which is often due to drugs, may cause ARF.
ARF can result from obstruction at any point in the urinary tract (see Fig. 14.12, p. 591). If there are two functioning kidneys, ureteric obstruction only causes uraemia if it is bilateral. A history of loin pain, haematuria, renal colic or difficulty in micturition suggests the diagnosis. Often the onset is clinically silent, and the obstruction is only discovered on investigation. An ultrasound examination of the kidneys and ureters should, therefore, be carried out in any patient with unexplained renal failure.
Clinical features
These reflect the causal condition, such as trauma, septicaemia or systemic disease, together with features associated with renal failure. Patients are usually oliguric (urine volume < 500 ml daily). Anuria (complete absence of urine) is rare and usually indicates acute urinary tract obstruction or vascular occlusion. In about 20% of cases, the urine volume is normal or increased, but with a low GFR and a reduction of tubular reabsorption (non-oliguric ARF). Excretion is inadequate despite good urine output, and the plasma urea and creatinine increase. In ARF, the rate of rise in plasma urea and creatinine is determined by the rate of catabolism (tissue breakdown). In ARF associated with severe infections, major surgery or trauma, the daily rise in plasma urea often exceeds 5 mmol/l.
Disturbances of water, electrolyte and acid-base balance arise. Hyperkalaemia is common, particularly with massive tissue breakdown, haemolysis or metabolic acidosis (see p. 289). Patients may have dilutional hyponatraemia if they have received inappropriate amounts of intravenous dextrose or have continued to drink freely despite oliguria. Metabolic acidosis develops unless prevented by loss of hydrogen ions through vomiting or aspiration of gastric contents. Hypocalcaemia, due to reduced renal production of 1,25-dihydroxycholecalciferol, is common.
At first the patient may feel well but, unless dialysis is instituted, clinical features linked to the retention of metabolic waste products eventually appear. Initially, these are anorexia, nausea and vomiting. Later, drowsiness, apathy and confusion, muscle-twitching, hiccoughs, fits and coma occur. The respiratory rate is increased due to acidosis, pulmonary oedema or respiratory infection. Pulmonary oedema (see Fig. 14.17) may result from the administration of excessive amounts of fluids and because of increased pulmonary capillary permeability. Anaemia is common and due to excessive blood loss, haemolysis or decreased erythropoiesis. There is a bleeding tendency due to disordered platelet function and disturbances of the coagulation cascade. Gastrointestinal haemorrhage may occur, often late in the illness, although this is less common with effective dialysis and the use of agents that reduce gastric acid production. Severe infections may complicate ARF because humoral and cellular immune mechanisms are depressed.


Figure 14.17 Pulmonary oedema in acute renal failure. The appearances are indistinguishable from left ventricular failure but the heart size is usually normal. Blood pressure is often high.
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Management
Emergency resuscitation
Hyperkalaemia (a plasma K+ concentration > 6 mmol/l) must be treated to prevent the development of life-threatening cardiac arrhythmias. This is detailed on pages 284-286.
The circulating blood volume, if low, must be corrected by transfusion with appropriate fluids. This may require monitoring of central venous or pulmonary wedge pressure. Patients with pulmonary oedema usually require dialysis to remove sodium and water.
Determination of the cause of ARF and specific treatment of the underlying cause
The cause may be obvious or revealed by simple initial investigations (e.g. ultrasound showing obstruction). If not, a range of investigations, including renal biopsy, may be necessary. In many cases, more than one factor contributes to the renal dysfunction.
There is no specific treatment for acute tubular necrosis. Some other causes of ARF may require specific therapy. Obstruction should be relieved urgently. Corticosteroids and immunosuppressive drugs are of value in ARF due to systemic vasculitis and some other causes of RPGN (see Box 14.14). Corticosteroids may also be indicated in acute tubulo-interstitial nephritis (see p. 617). Control of blood pressure is critical in ARF due to accelerated hypertension (see p. 611). Plasma infusion and plasma exchange may be indicated in microangiopathic diseases (see p. 610).
If pelvic or ureteric dilatation is found, percutaneous nephrostomy is undertaken to decompress the urinary system (see p. 584). Dialysis can usually be avoided. Injection of dye through the nephrostomy tube (antegrade pyelography) reveals the site of the obstruction.
Once obstruction has been relieved and blood chemistry has returned towards normal, the underlying cause is identified and treated wherever possible (see p. 590). Sometimes obstruction is caused by pelvic malignancies, such as carcinoma of the cervix, uterus or colon, which are so advanced that intervention is inadvisable.
General management of established ARF
In established ARF the aims are to control fluid and electrolyte balance, maintain nutrition, control the biochemical abnormalities and protect the patient from infection. Drugs must be used with particular care. Renal replacement therapy may be required (see p. 605).
Fluid and electrolyte balance. After initial resuscitation, daily fluid intake should equal urine output, plus an additional 500 ml to cover insensible losses; such losses are higher in febrile patients and in tropical climates. Since sodium and potassium are retained, intake of these substances should be restricted. If abnormal losses occur, as in diarrhoea, additional fluid and electrolytes are required. The patient should be weighed daily. Large changes in body weight, or the development of oedema or signs of fluid depletion indicate that fluid intake should be reassessed.
Protein and energy intake. In patients where dialysis is likely to be avoided, dietary protein is restricted to about 40 g/day. Attempts are made to suppress endogenous protein catabolism by giving as much energy as possible in the form of fat and carbohydrate. Patients treated by dialysis may have more protein (70 g protein daily, 10-12 g nitrogen). In some patients, feeding via a nasogastric tube may be helpful. Parenteral nutrition (see p. 317) may be required because of vomiting or diarrhoea, or if the bowel is not intact, or to give adequate energy and nitrogen to hypercatabolic patients.
Recovery from acute renal failure
This is usually indicated by a gradual return of urine output, and subsequently a steady improvement in plasma biochemistry towards normal. Some patients, primarily those with acute tubular necrosis or after relief of chronic urinary obstruction, develop a 'diuretic phase'. Fluid should be given to replace the urine output as appropriate. Supplements of sodium chloride, sodium bicarbonate and potassium chloride, and sometimes calcium, phosphate and magnesium, may be needed to compensate for increased urinary losses. After a few days urine volume falls to normal as the concentrating mechanism and tubular reabsorption are restored.
Prognosis
In uncomplicated ARF, such as that due to simple haemorrhage or drugs, mortality is low even when renal replacement therapy is required. In ARF associated with serious infection and multiple organ failure, mortality is 50-70%. Outcome is usually determined by the severity of the underlying disorder and other complications, rather than by renal failure itself. Issues relating to ARF in older people are outlined below.
ISSUES IN OLDER PEOPLE
ACUTE RENAL FAILURE
Nephrons decline in number from the age of 30; creatinine clearance declines at a rate of about 10 ml/min per decade after the age of 50 years.
As muscle mass also falls with age, less creatinine is produced each day. Serum creatinine can thus be a misleading guide to renal function in poorly nourished older people with low muscle mass.
The renal tubules also undergo age-related changes, leading to loss of urinary concentration, acidification and toxin secretion.
Older people are more likely to take drugs which may contribute to loss of renal function, such as diuretics, ACE inhibitors and NSAIDs.
Due to this reduction in function, older people are more prone to acute renal failure; infection, renal vascular disease, prostatic obstruction, hypovolaemia and severe cardiac dysfunction are common contributory causes.
The most important cause of renal disease in older people is vascular, and the kidneys are thus highly susceptible to any hypotensive episode.
The mortality from acute renal failure rises with age, primarily because of comorbid conditions.


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CHRONIC RENAL FAILURE
Chronic renal failure (CRF) refers to an irreversible deterioration in renal function which classically develops over a period of years. Initially, it is manifest only as a biochemical abnormality. Eventually, loss of the excretory, metabolic and endocrine functions of the kidney leads to the development of the clinical symptoms and signs of renal failure, which are referred to as uraemia. When death is likely without renal replacement therapy it is called end-stage renal failure (ESRF).
The social and economic consequences of CRF are considerable. In the UK 85-95 new patients per million of the adult population are accepted for long-term dialysis treatment each year (see Fig. 14.18); the availability of dialysis and transplantation has transformed the outlook for such patients. The incidence of CRF is much higher in some other countries due to differences in regional and racial incidences of disease as well as because of differences in medical practice.
Aetiology


Figure 14.18 Haemodialysis unit. Six of 19 stations, a mixture of beds and chairs, in an outpatient haemodialysis unit. Each station treats three patients daily and therefore six patients in total (each attending three times weekly).
CRF may be caused by any condition which destroys the normal structure and function of the kidney. Important causes are shown in Box 14.15. A presumptive diagnosis of a chronic form of glomerulonephritis may be made if there is proteinuria, haematuria and hypertension in the absence of any other cause of renal failure, but a precise diagnosis is not always established. Patients often have bilateral small kidneys, and in such a situation renal biopsy is usually inadvisable because of the difficulty in making a histological diagnosis in severely damaged kidneys and the fact that treatment is unlikely to improve renal function significantly.
Pathogenesis
Disturbances in water, electrolyte and acid-base balance contribute to the clinical picture in patients with chronic renal failure, but the exact pathogenesis of the clinical syndrome of uraemia is unknown. Many substances present in abnormal concentration in the plasma have been suspected as being 'uraemic toxins', and uraemia is probably caused by the accumulation of various intermediary products of metabolism.
Clinical features
Renal failure may present as a raised blood urea and creatinine found during routine examination, often accompanied by hypertension, proteinuria or anaemia. When renal function deteriorates slowly patients may remain asymptomatic until the GFR is 20 ml/min or less (normal range 80-120 ml/min; see Fig. 14.5, p. 582). Nocturia, due to the loss of concentrating ability and increased osmotic load per nephron, is often an early symptom. Thereafter, due to the widespread effects of renal failure, symptoms and signs may develop related to almost every body system (see Fig. 14.19). Patients may present with complaints which are not obviously renal in origin, such as tiredness or breathlessness.
14.15 IMPORTANT CAUSES OF CHRONIC RENAL FAILURE
Disease Proportion of end-stage renal failure Comments
Congenital and inherited 5% e.g. Polycystic kidney disease, Alport's syndrome
Renal artery stenosis 5%
Hypertension 5-25% It is uncertain whether such variation is due to true racial differences or to differences in diagnostic labelling
Glomerular diseases 10-20% IgA nephropathy is most common
Interstitial diseases 5-15%
Systemic inflammatory diseases 5% e.g. SLE, vasculitis
Diabetes mellitus 20-40% Large racial and national differences exist-the higher rate is from the USA
Unknown 5-20%

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Figure 14.19 Physical signs in chronic renal failure. (* Features of renal replacement therapy)
In end-stage renal failure (creatinine clearance < 5 ml/min) patients appear ill and anaemic. They do not necessarily retain fluid, and may show signs of sodium and water depletion. There may be unusually deep respiration related to metabolic acidosis (Kussmaul's respiration), anorexia and nausea. Later, hiccoughs, pruritus, vomiting, muscular twitching, fits, drowsiness and coma ensue.
Anaemia
Anaemia is common; it usually correlates to the severity of renal failure and contributes to many of the non-specific symptoms of CRF. Several mechanisms are implicated, including:
relative deficiency of erythropoietin
diminished erythropoiesis due to the toxic effects of uraemia on marrow precursor cells
reduced red cell survival
increased blood loss due to capillary fragility and poor platelet function
reduced dietary intake and absorption of iron and other haematinics.

Plasma erythropoietin is usually within the normal range and thus inappropriately low for the degree of anaemia. In patients with polycystic kidneys, anaemia is often less severe or absent, and in some interstitial disorders it appears disproportionately severe for the degree of renal failure. This is probably because of the effects of these disorders on the interstitial fibroblasts that secrete erythropoietin.
Renal osteodystrophy
This metabolic bone disease which accompanies CRF consists of a mixture of osteomalacia, hyperparathyroid bone disease (osteitis fibrosa), osteoporosis and osteosclerosis (see Fig. 14.20). Osteomalacia (see p. 1029) results from diminished activity of the renal 1-a-hydroxylase enzyme, with failure to convert cholecalciferol to its active metabolite 1,25-dihydroxycholecalciferol. A deficiency of the latter leads to diminished intestinal absorption of calcium, hypocalcaemia and reduction in the calcification of osteoid. Osteitis fibrosa results from secondary hyperparathyroidism. The parathyroid glands are stimulated by the low plasma calcium, and also by hyperphosphataemia. In some patients tertiary or autonomous hyperparathyroidism with hypercalcaemia develops. Osteoporosis occurs in many patients, possibly related to malnutrition. Osteosclerosis is seen mainly in the sacral area, at the base of the skull and in the vertebrae; the cause of this unusual reaction is not known.
Myopathy
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Figure 14.20 Pathogenesis of renal osteodystrophy. The net result of decreased 1,25 (OH)2 D3 levels and increased parathyroid hormone (PTH) levels is bone which exhibits increased osteoclastic activity and increased osteoid as a consequence of decreased mineralisation.
Generalised myopathy is due to a combination of poor nutrition, hyperparathyroidism, vitamin D deficiency and disorders of electrolyte metabolism. Muscle cramps are common, and quinine sulphate may be helpful. The 'restless leg syndrome', where the patient's legs are jumpy during the night, may be troublesome and is often improved by clonazepam.
Neuropathy
This results from demyelination of medullated fibres with the longer fibres being involved at an earlier stage. Sensory neuropathy may cause paraesthesiae. Motor neuropathy may present as foot drop. Uraemic autonomic neuropathy may cause delayed gastric emptying, diarrhoea and postural hypotension. Clinical manifestations of neuropathy appear late in the course of chronic renal failure but may improve or even resolve once dialysis is established.
Endocrine function
A number of hormonal abnormalities may be present, of which the most important are hyperprolactinaemia and hyperparathyroidism. In women, amenorrhoea is common. In both sexes there is loss of libido and sexual function, at least in part related to hyperprolactinaemia and galactorrhoea (see p. 739). Treatment with bromocriptine is sometimes useful.
The half-life of insulin is prolonged in CRF due to reduced tubular metabolism of insulin; insulin requirements may therefore decline in diabetic patients in end-stage CRF. However, there is also a post-receptor defect in insulin action, leading to relative insulin resistance. This latter abnormality is improved by dialysis treatment. Changes in carbohydrate metabolism depend on which factors predominate.
Cardiovascular disorders
Hypertension develops in approximately 80% of patients with CRF. In part, this is caused by sodium retention. Chronically diseased kidneys also tend to hypersecrete renin, leading to high circulating concentrations of renin, angiotensin II and aldosterone. This is exaggerated if there is renal under-perfusion related to renal vascular disease. Hypertension must be controlled, as it causes further vascular and glomerular damage and worsening of renal failure. Atherosclerosis is common and may be accelerated by hypertension. Vascular calcification may develop and be sufficiently severe to cause limb ischaemia. Pericarditis is common in untreated or inadequately treated end-stage renal failure. It may lead to pericardial tamponade and, later, constrictive pericarditis.
Acidosis
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Declining renal function is associated with metabolic acidosis (see p. 289), which is often asymptomatic. Sustained acidosis results in protons being buffered in bone in place of calcium, thus aggravating metabolic bone disease. Acidosis may also contribute to reduced renal function and increased tissue catabolism. The plasma bicarbonate should be maintained above 18 mmol/l by giving sodium bicarbonate supplements. The dose is determined by clinical trial, commencing with 1 g 8-hourly and increasing as required. The increased sodium intake may induce hypertension or oedema; calcium carbonate (up to 3 g daily) is an alternative agent that is also used to bind dietary phosphate.
Infection
Cellular and humoral immunity are impaired, with increased susceptibility to infection. Infections are the second most common cause of death in dialysis patients, after cardiovascular disease.
Bleeding
There is an increased bleeding tendency in renal failure which manifests in patients with advanced disease as cutaneous ecchymoses and mucosal bleeds. Platelet function is impaired and bleeding time prolonged. Adequate dialysis treatment partially corrects the bleeding tendency.
Gastrointestinal disorders
Anorexia followed by nausea and vomiting (especially in the morning) is commonly seen. There is a higher incidence of peptic ulcer disease in uraemic patients.
Management
There are several aspects to the management of CRF:
Identify the underlying renal disease.
Attempt to prevent further renal damage.
Look for reversible factors which are making renal function worse (see Box 14.16).
Attempt to limit the adverse effects of the loss of renal function.
Institute renal replacement therapy (dialysis, transplantation) when appropriate.

At presentation the nature of the underlying disease should be determined, if possible, by history, examination, testing of biochemistry, immunology, radiology and biopsy. The degree of renal failure is assessed and complications are documented. In some cases the cause may be amenable to specific therapy, e.g. immunosuppression in some types of glomerulonephritis. A search is made for reversible factors, correction of which results in improved renal function (see Box 14.16).
14.16 REVERSIBLE FACTORS IN CHRONIC RENAL FAILURE
Hypertension
Reduced renal perfusion
Renal artery stenosis
Hypotension due to drug treatment
Sodium and water depletion
Poor cardiac function
Urinary tract obstruction
Urinary tract infection
Other infections: increased catabolism and urea production
Nephrotoxic medications


In patients with irreversible renal failure, various measures can reduce symptoms and may slow progression to end-stage renal failure.
Retarding the progression of CRF
Unless dialysis or transplantation is provided, CRF is eventually fatal. Once the plasma creatinine exceeds about 300 µmol/l, there is usually progressive deterioration in renal function, irrespective of aetiology. The rate of deterioration is very variable between patients but is relatively constant for an individual patient. A plot of the reciprocal of the plasma creatinine concentration against time allows the physician to predict when dialysis will be required and to detect any unexpected worsening of renal failure (see Fig. 14.21). Changes in the slope may reflect changes in treatment-for instance, blood pressure control or other interventions.


Figure 14.21 Plot of the reciprocal of serum creatinine concentration against time over a 6-year period in a patient with progressive renal failure caused by membranous nephropathy. Serial plasma creatinine estimations permit prediction of the time to end-stage renal disease. The 'break point' (arrow) at which the gradient of the line is dramatically reduced was associated with a 6-month course of treatment with chlorambucil and prednisolone.
Control of blood pressure
In many types of renal disease, but particularly in diseases affecting glomeruli, control of blood pressure may retard the rate of deterioration of GFR. This has been proven for diabetic nephropathy, but is probably true for other diseases as well, particularly those associated with heavy proteinuria. No threshold for this effect has been found; reduction of any level of blood pressure is beneficial. Various target blood pressures have been suggested-for example, 130/85 mmHg for CRF alone, lowered to 125/75 mmHg for those with proteinuria greater than 1 g/day. Achieving these targets often requires multiple drugs and may be limited by toxicity or non-compliance. The very high incidence of left ventricular hypertrophy, heart failure and occlusive vascular disease in patients with long-standing renal disease also justifies vigorous efforts to control blood pressure.
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ACE inhibitors have been shown to be more effective at retarding the progression of renal failure than other therapies giving an equal lowering of systemic blood pressure (see EBM panel). This may be because they reduce glomerular perfusion pressure by dilating the efferent arteriole, an effect which causes an immediate reduction in GFR when therapy is initiated. Reduction in proteinuria is a good prognostic sign, but it is not clear if this is causally related to prognosis. Apart from ACE inhibitors, angiotensin II receptor antagonists also reduce glomerular perfusion pressure, and the same effect may be achieved by certain non-dihydropyridine calcium antagonists.
EBM
CHRONIC RENAL FAILURE (CRF)-role of angiotensin-converting enzyme (ACE) inhibitors in non-diabetic patients
'In non-diabetic patients with hypertension, CRF and proteinuria, ACE inhibitors reduce proteinuria and slow the rate of loss of renal function. This effect is probably shared by angiotensin receptor antagonists. The effect is greater than with alternative hypotensive agents and is independent of blood pressure reduction.'
(See p. 674 for an EBM panel on the role of ACE inhibitors in diabetic subjects with renal disease.)
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329:1456-1462.
Lovell HG. Angiotensin-converting enzyme inhibitors in normotensive diabetic patients with microalbuminuria (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Ihle BU, Whitworth JA, Shahinfar S, et al. Angiotensin-converting enzyme inhibition in non-diabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis 1996; 27:489-495.
Further information: www.cochrane.co.uk

Diet
EBM
CHRONIC RENAL FAILURE-role of dietary protein restriction
'Although the single largest controlled trial did not demonstrate a significant overall effect, subsequent subgroup analysis and two meta-analyses of published RCTs suggest that restriction of dietary protein intake delays the progression of chronic renal failure in non-diabetic subjects and in insulin-dependent diabetes mellitus. In non-diabetic subjects the occurrence of end-stage renal failure is reduced by about 40% compared with unrestricted protein intake. Trials have used between 0.3 and 0.8 g/kg, and do not allow definition of the optimum intake.'
Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330:877-884.
Fouque D, Wang P, Laville M, Boissel JP. Low protein diets for chronic renal failure in non diabetic adults (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Waugh NR, Robertson AM. Protein restriction for diabetic renal disease (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk

In experimental studies, progressive renal disease can be retarded by various manipulations of diet, most notably by restriction of dietary protein. In human studies results have been less clear-cut (see EBM panel); low-protein diets are difficult to adhere to and carry a risk of inducing malnutrition. This remains a controversial area but, for most patients living in areas where renal replacement therapy is available, severe protein restriction is not generally recommended. Moderate restriction (to 60 g protein per day) should be accompanied by an adequate intake of calories to prevent malnutrition. Anorexia and muscle loss may indicate a need to commence dialysis treatment.
Lipids
Hypercholesterolaemia is almost universal in patients with significant proteinuria, and increased triglyceride levels are also common in patients with CRF. As well as influencing the development of vascular disease, it has been suggested that this may accelerate the progression of chronic renal disease. The introduction of HMG CoA reductase inhibitors (see p. 311) has made it possible to achieve substantial reductions in lipids in chronic renal disease, but there have been no long-term studies in this group of patients. However, many believe that the high incidence of vascular disease in CRF justifies the treatment of these abnormalities in advance of proof from controlled trials.
Electrolytes and fluid
Due to the reduced ability of the failing kidney to concentrate the urine, a relatively high urine volume is needed to excrete products of metabolism and a fluid intake of around 3 l/day is desirable. Some patients with so-called 'salt-wasting' disease may require a high sodium and water intake, including supplements of sodium chloride and sodium bicarbonate, to prevent fluid depletion and worsening of renal function. This is most often seen in patients with renal cystic disease, obstructive uropathy, reflux nephropathy or other tubulo-interstitial diseases and is not seen in patients with glomerular disease. These patients benefit from taking 5-10 g/day (85-170 mmol/day) of sodium chloride by mouth. It is usual to start with 2-3 g/day and increase the dose as required. The limit for additional salt is set by the development of peripheral or pulmonary oedema, or aggravation of hypertension. Sodium bicarbonate may be substituted in part for sodium chloride when acidosis requires correction.
Limitation of potassium intake (e.g. 70 mmol/day) and sodium intake (e.g. 100 mmol/day) may be required in late CRF if there is evidence of accumulation. Disproportionate fluid retention in milder renal failure, sometimes leading to episodic pulmonary oedema, is particularly associated with renal artery stenosis.
Anaemia
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Recombinant human erythropoietin is effective in correcting the anaemia of CRF. Therapy is usually directed towards achieving a target haemoglobin of between 10 and 12 g/l. It must be injected, and subcutaneous administration is most effective. Complications of treatment include increased blood pressure, and adjustment of antihypertensive medication is often necessary. There is also an increase in blood coagulability and an increased incidence of thrombosis of the arteriovenous fistulae used for haemodialysis. If anaemia is corrected slowly, these effects are less common. Erythropoietin is less effective in the presence of iron deficiency, active inflammation or malignancy, or in patients with aluminium overload which may occur in dialysis. These factors should be sought and, if possible, corrected before treatment.




Integration link: Erythropoietin supplementation in renal failure

Taken from Pharmacology 5e




Osteodystrophy
Plasma calcium and phosphate should be kept as near to normal as possible. Hypocalcaemia is corrected by giving 1-a-hydroxylated synthetic analogues of vitamin D. The dose is adjusted to avoid hypercalcaemia. This will usually prevent or control osteomalacia, although it is sometimes resistant, presumably because of other factors inhibiting bone mineralisation. Hyperphosphataemia is controlled by dietary restriction of foods with high phosphate content (milk, cheese, eggs) and the use of phosphate-binding drugs. These agents form insoluble complexes with dietary phosphate and prevent its absorption (e.g. calcium carbonate 500 mg with each meal). Aluminium hydroxide also has a phosphate-binding effect (aluminium hydroxide capsules 300-600 mg before each meal). To prevent aluminium toxicity, the dose of aluminium hydroxide should be kept to a minimum and administered immediately before meals. Secondary hyperparathyroidism is usually prevented or controlled by these measures but, in severe bone disease with autonomous parathyroid function, parathyroidectomy may become necessary.




Integration link: Clinical use of calcium salts

Taken from Pharmacology 5e




Prognosis
The tendency of renal impairment to progress was described above (see Fig. 14.21), along with ways of influencing that progression.
Information about the long-term prognosis for patients on dialysis or following transplantation is limited because these techniques have been available only for the past 30 years and technology is changing rapidly. Nevertheless, dialysis and transplantation can be considered as highly effective forms of treatment, with a 5-year survival of approximately 80% for home haemodialysis, 80% following renal transplantation, 60% for hospital haemodialysis and 50% for continuous ambulatory peritoneal dialysis (CAPD). These figures are not directly comparable because of patient selection-many older patients and those with systemic diseases such as diabetes mellitus are treated by CAPD. They also conceal a very large increase in death rates from certain causes, but particularly vascular disease, in comparison with an age-matched population. However, they indicate how the prognosis of end-stage renal disease is now much better than that of many other potentially fatal diseases.

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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > RENAL REPLACEMENT THERAPY
RENAL REPLACEMENT THERAPY
Since the 1960s the facility to replace certain functions of the kidney by artificial means has been available to physicians. Initially, this was applied primarily in ARF, but it has now become routine in patients with end-stage renal failure, who account for the vast majority of treatments. These treatments do not replace the endocrine and metabolic functions of the kidney. They do, however, achieve control of plasma biochemistry and the facility to remove fluid from the circulation (ultrafiltration). The prototype renal replacement therapy was haemodialysis, which is still the most common modality, but a variety of other strategies have evolved, particularly for treating unstable patients with ARF (see Box 14.17).
RENAL REPLACEMENT IN ACUTE RENAL FAILURE
The indications for renal replacement therapy in ARF are as follows:
Increased plasma urea: in general, a plasma urea greater than 30 mmol/l and creatinine greater than 600 µmol/l are undesirable, but much depends on factors such as the rate of biochemical deterioration and the risks of dialysis for the patient involved.
Hyperkalaemia: while this can usually be controlled by medical measures in the short term (see pp. 285-286), dialysis is often required for definitive control.
Fluid overload: if not controlled by fluid restriction and diuretics.
Uraemic pericarditis (uncommon in ARF).

The principal options for renal replacement in ARF are haemodialysis, high-volume haemofiltration, continuous arteriovenous or venovenous haemofiltration, and peritoneal dialysis.
Haemodialysis
Although continuous techniques are being used increasingly in the management of ARF, intermittent haemodialysis is still an important treatment modality in most renal units. In ARF most patients can be treated by 3-4 hours of haemodialysis, either daily in catabolic patients or on alternate days. Dialysis regimens are adjusted to maintain a pre-dialysis urea concentration less than 30 mmol/l, adequate control of potassium and phosphate, and normal ECF volume status.
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14.17 TYPES OF ARTIFICIAL RENAL REPLACEMENT THERAPY
Application Typical duration Typical frequency Dialysis membrane Access device
Treatments involving circulation of blood outside the body, regulated by machine
Haemodialysis ARF 3-5 hrs Often daily, sometimes alternate days Synthetic polymer Dual-lumen central vein catheter
CRF 3-5 hrs 3 times per week Synthetic polymer Dual-lumen central vein catheter or peripheral arteriovenous fistula
High-volume haemofiltration ARF 4-6 hrs (15-30 l of filtrate replaced) Often daily, sometimes alternate days High-flux synthetic polymer Dual-lumen central vein catheter
Continuous venovenous haemofiltration (CVVH) ARF (unstable patients, e.g. in intensive care unit) Continuous for as long as necessary 1-2 l of filtrate replaced per hour High-flux synthetic polymer Dual-lumen central vein catheter
Continuous arteriovenous haemofiltration (CAVH) ARF (unstable patients, e.g. in intensive care unit) Continuous for as long as necessary Continuous- 1-2 l of filtrate replaced per hour High-flux synthetic polymer Peripheral arterial and venous cannulae
Treatments involving instillation of fluid into the peritoneal cavity
Continuous ambulatory peritoneal dialysis (CAPD) CRF Continuous 4-5 × 2 l fluid exchanges daily Peritoneal membrane Soft intraperitoneal catheter ('Tenckhoff' catheter)
Automated peritoneal dialysis CRF Overnight (often with single day-time exchange too) 4-5 fluid exchanges by machine Peritoneal membrane 'Tenckhoff' catheter
Acute peritoneal dialysis ARF Continuous Hourly fluid exchanges manually or by machine Peritoneal membrane Rigid peritoneal catheter

Vascular access is most often obtained by means of a double-lumen catheter placed in a major vein, commonly the internal jugular, subclavian or femoral. The lifespan of these catheters is often limited due to thrombosis or infection. The Scribner shunt is now rarely used. This consisted of Teflon tips and siliconised rubber tubing placed to connect an artery and a vein at the ankle or wrist. The tubing was then separated for connection to the dialyser.
Anticoagulation is required to prevent clotting of the extracorporeal circuit. Haemodialysis machines are equipped to infuse heparin; the efficiency of anticoagulation is monitored by the activated clotting time (ACT). Recent studies have suggested that the use of epoprostenol (prostacyclin) for anticoagulation is associated with a lower risk of bleeding on dialysis, and many units use this in selected patients.
High-volume haemofiltration
This technique involves the rapid removal and replacement of 15-30 l of plasma ultrafiltrate over 3-5 hours, using an artificial membrane with a very high ultrafiltration capacity, on a daily or alternate-day basis. The fluid removed is replaced by haemofiltration fluid. It is claimed that this technique induces less circulatory instability than haemodialysis.
Continuous techniques


Figure 14.22 Continuous venovenous haemofiltration (CVVH) on an intensive care unit. In this hypothermic patient the haemofilter and blood lines have been wrapped to reduce heat loss.
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These include continuous arteriovenous haemofiltration (CAVH) and continuous venovenous haemofiltration (CVVH-see Fig. 14.22). These systems cause less haemodynamic disturbance than conventional haemodialysis, and are widely used in patients with ARF who are unstable and require intensive care (see Fig. 14.16, p. 596). In CAVH the extracorporeal blood circuit is driven by the arteriovenous pressure difference. Poor filtration rates and clotting of the filter may result from low arterial pressure and/or elevated central venous pressure. CVVH is pump-driven, allowing a reliable extracorporeal circulation. Most patients are managed by removal and replacement of 1-2 l of filtrate per hour (equivalent to a GFR of 15-30 ml/min).
Peritoneal dialysis
In ARF, this technique has been supplanted in most centres by those outlined above. It is less efficient than haemodialysis, and seldom achieves good biochemical control, especially in catabolic patients. It is not feasible after recent abdominal surgery, but can be useful in patients with cardiovascular instability (e.g. after cardiac surgery). A trocar and cannula system is used for acute peritoneal access, and 0.5-2 l volumes of peritoneal dialysis fluid are infused and drained cyclically. Flow can be regulated manually or by an automatic cycler. Cloudy effluent indicates the development of peritonitis, in which case the catheter should be removed immediately and appropriate antibiotics given (e.g. vancomycin or gentamicin).
RENAL REPLACEMENT IN CHRONIC RENAL FAILURE
Haemodialysis


Figure 14.23 Haemodialysis. A patient receiving haemodialysis through a forearm subcutaneous fistula (a Brescia-Cimino fistula). She subsequently received a live related transplant.
Intermittent haemodialysis is the standard blood purification therapy in end-stage renal failure (ESRF-see Fig. 14.23). Haemodialysis should be started when, despite adequate medical treatment, the patient has advanced renal failure, and before he or she develops serious complications. This often occurs with a plasma creatinine of 600-800 µmol/l. Vascular access is required; an arteriovenous fistula should be formed, usually in the forearm, when the serum creatinine is around 400 µmol/l, so that it has time to become established. After 4-6 weeks, increased pressure in the veins leading from the fistula will have caused distension and thickening of the vessel wall (arterialisation). Large-bore needles can then be inserted into the vein to provide access for each haemodialysis treatment (see Fig. 14.23). If this is not possible, plastic cannulae in central veins can be used for short-term access. Haemodialysis is usually carried out for 3-5 hours three times weekly. Most patients notice a gradual improvement in symptoms during the first 6 weeks of treatment. Plasma urea and creatinine are lowered by each treatment but do not return to normal. Accepted standards of dialysis adequacy, which relate the clearance of urea to total body water, are adhered to in most units. Some patients are able to carry out their treatment at home. Many patients lead normal and active lives, and patient survival for more than 20 years is commonplace.
Continuous ambulatory peritoneal dialysis (CAPD)
CAPD is a form of long-term dialysis involving insertion of a permanent Silastic catheter into the peritoneal cavity. Two litres of sterile, isotonic dialysis fluid are introduced and left in place for a period of approximately 6 hours. During this time, metabolic waste products diffuse from peritoneal capillaries into the dialysis fluid down a concentration gradient. The fluid is then drained and fresh dialysis fluid introduced. This cycle is repeated four times daily, during which time the patient is mobile and able to undertake normal daily activities. It is particularly useful in young children, in elderly patients with cardiovascular instability and in patients with diabetes mellitus. Its long-term use may be limited by episodes of bacterial peritonitis, but some patients have been treated successfully for more than 10 years.
The use of automated peritoneal dialysis (APD) is now widespread. This system is similar to CAPD but uses a mechanical device to perform the fluid exchanges during the night, leaving the patient free or with only a single exchange to perform during the day.
Renal transplantation
This offers the possibility of restoring normal kidney function and correcting all the metabolic abnormalities of CRF. The kidney graft is taken from a cadaver donor or from a relative. ABO (blood group) compatibility between donor and recipient is essential, and it is usual to select donor kidneys on the basis of human leucocyte antigen (HLA) matching as this improves graft survival. Immune-mediated graft rejection is the major cause of failure. Results of kidney transplantation have improved significantly in recent years. Three-year graft survival is in the region of 80%, while 3-year patient survival is approximately 90%.
Long-term immunosuppressive therapy is required following renal transplantation. Many therapeutic regimens have been used, but the most common involves a combination of prednisolone, ciclosporin A and azathioprine. There is concern about the long-term nephrotoxicity of ciclosporin. The role of newer immunosuppressive agents such as tacrolimus (FK506), mycophenolate mofetil and rapamycin is currently being established by clinical trials.
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Immunosuppression is associated with an increased incidence of infection, particularly opportunistic, and an increased risk of malignant neoplasms, especially of the skin. Approximately 50% of white patients will have developed skin malignancy by 15 years post-transplant. Lymphomas are rare but occur early and are often related to infection with herpes virus, especially Epstein-Barr virus (see p. 16). Despite these drawbacks, transplantation offers the best hope of complete rehabilitation and is the most cost-effective of the treatment options for chronic renal failure.
ISSUES IN OLDER PEOPLE
RENAL REPLACEMENT THERAPY
Age itself is not a barrier to good quality of life on renal replacement therapy.
The high prevalence of coexisting cardiovascular disease in old age can make dialysis difficult; the elderly are more sensitive to fluid balance changes, predisposing to hypotension during dialysis with rebound hypertension between dialyses. In addition the ischaemic heart cannot cope with fluid overload and pulmonary oedema easily develops.
This means that only hospital-provided haemodialysis is suitable and older patients require more medical and nursing time.
Survival on dialysis is difficult to predict for an individual patient, but is independently correlated with age, functional ability (e.g. Barthel or Karnofsky score) and comorbid disease.
Withdrawal from dialysis is a common cause of death in older patients with comorbid disease.
Relative risks of surgery and immunosuppression, and limited organ availability exclude most older people from transplantation.
Conservative therapy, i.e. without dialysis but with adequate support, may be a popular option for patients at high risk of complications from dialysis, who have a limited prognosis and little hope of functional recovery.


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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > CONGENITAL ABNORMALITIES OF THE KIDNEYS AND URINARY SYSTEM
CONGENITAL ABNORMALITIES OF THE KIDNEYS AND URINARY SYSTEM
Congenital anomalies of the urinary tract (see Fig. 14.24) affect more than 10% of infants and, if not immediately lethal, may lead to complications in later life. About 1 in 500 infants are born with only one kidney. Although usually compatible with normal life, this is often associated with other abnormalities. Polycystic kidney disease (see p. 621) is the most common inherited cause of severe renal disease. The next most common, Alport's syndrome, is considered on page 611 and other cystic diseases on page 622. Other inherited disorders affecting the kidney include tumour syndromes (see p. 635) and conditions caused by mutations in transporter or exchanger molecules (see p. 623).
Hypospadias is caused by a failure of fusion of embryonic folds and results in abnormal placing of the external urinary meatus on the ventral surface of the penis. The opening may be coronal, penile, scrotal or even perineal. With opening in these latter sites, the corpus spongiosum is scarred and fibrosed, leading to a ventral curvature or chordee of the penis. The aim of treatment is to correct the chordee by excising the fibrosis and then to perform a plastic surgical operation to make a new urethral opening in the normal position on the glans. This procedure should be completed before the boy reaches school age.


Figure 14.24 Congenital abnormalities of the urinary tract.
Epispadias refers to a condition where the external urinary meatus opens on the dorsal surface of the penis. The extent of the malformation varies from an isolated penile abnormality to a gross failure in the development of the bladder and urethra. Severe deformity results from extension of the cloacal membrane on to the lower abdominal wall, preventing the two halves of the wall from closing over the developing bladder. As a result, the mucosa of the bladder and the ureteric orifices are exposed and form the infra-umbilical part of the abdominal wall (exstrophy). The urethra lies opened out and the testes are undescended; additional abnormalities include separation of the symphysis pubis and rectal prolapse. Reconstruction of these deformities is not always successful and urinary incontinence may remain a major problem and require urinary diversion.
A ureterocele (see Fig. 14.12, p. 591) develops behind a pin-hole ureteric orifice; the intramural part of the ureter dilates and bulges into the bladder, and can become very large. Incision of the pin-hole opening relieves the obstruction.
An ectopic ureter occurs with congenital duplication of one or both kidneys (duplex kidneys). Developmentally, the ureter has two main branches and, if this arrangement persists, the two ureters of the duplex kidneys may drain separately into the bladder. One ureter enters normally on the trigone, while the ectopic ureter (from the upper renal moiety) enters the bladder or, more rarely, the vagina or seminal vesicle.
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A ureter that is ectopic and drains into the bladder is liable to have an ineffective valve mechanism so that urine passes up the ureter on voiding (vesico-ureteric reflux, see p. 620). Reflux can occur in normally sited ureters if the intramural ureter fails to act as a valve. The pressure of refluxing urine behaves as an intermittent obstruction which in children may lead to serious renal damage. The management of vesico-ureteric reflux and associated reflux nephropathy is outlined on page 621.
In primary obstructive megaureter there is dilatation of the ureter in all but its terminal segment without obvious cause and without vesico-ureteric reflux. Radiographic and pressure/flow studies may be needed to determine whether there is obstruction to urine flow. Narrowing of the ureter and reimplantation may be necessary.

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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > RENAL VASCULAR DISEASES
RENAL VASCULAR DISEASES
Adequate blood supply is critical for all aspects of renal function. Hence, diseases which affect the renal blood vessels can cause any and all of the clinical manifestations of renal disease. They are particularly likely to cause acute or chronic renal failure and secondary hypertension.
RENAL ARTERY STENOSIS
While disease of the renal arteries is a well-known cause of secondary hypertension, it is also an increasingly recognised cause of renal failure, particularly in the elderly-a condition known as ischaemic nephropathy.
Pathology
The most common cause is atherosclerosis, especially in older patients; it is usually associated with clinically significant atherosclerosis elsewhere, and is particularly likely if there are symptoms or signs of disease affecting the lower limbs. In younger patients (< 50 years), fibromuscular dysplasia is a more likely cause. This is a congenital band of fibrous tissue around the artery, which, as the patient grows, causes progressive narrowing of the vessel. It most commonly presents with hypertension in patients aged 15-30 years. In both types, if the stenosis is haemodynamically significant, an area of post-stenotic dilatation develops distal to the narrowed area. Stenosis is classed as ostial, proximal or distal according to the part of the vessel affected, and is quantified in terms of the degree of narrowing. Stenosis of less than 50% is not usually considered to be haemodynamically significant. In simple, unilateral disease the unaffected kidney will show changes of hypertensive nephrosclerosis; the renal parenchyma on the stenosed side may be relatively protected from the effects of hypertension, but will have a reduced GFR due to under-perfusion. In atherosclerosis the picture is often complicated by small-vessel disease in the kidneys that may be related to subclinical atheroemboli, hypertension or other disease.
Investigations
14.18 RENAL ARTERY STENOSIS
Renal artery stenosis is more likely if:
Hypertension is severe, or of recent onset, or difficult to control
Kidneys are asymmetrical in size
There is evidence of vascular disease elsewhere (especially in lower limbs)




Figure 14.25 Renal artery stenosis. A Digital subtraction arteriogram following injection of contrast material into the aorta showing renal artery stenosis. The abdominal aorta is severely irregular and atheromatous. The right renal artery is absent. The left renal artery is stenosed (arrow), but contrast medium has passed the stenosis and the developing nephrogram can be seen. B In another patient, a catheter has been passed beyond a stenosis at the ostium of the right renal artery in preparation for balloon dilatation/stenting.
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If the stenosis is long-standing, a reduction in kidney size occurs which can be detected by ultrasound. Since renal artery stenosis is often asymmetrical or unilateral, a discrepancy in size between the two kidneys on ultrasound is a useful (but insensitive and late) pointer to the diagnosis, along with hypertension, renal impairment or vascular disease elsewhere (see Box 14.18). Renal isotope scanning may show delayed uptake of isotope and reduced excretion by an affected kidney. The definitive investigation is renal arteriography (see Fig. 14.25) and this is required before treatment is undertaken.
Management and prognosis
Untreated, atheromatous renal artery stenosis will progress to complete arterial occlusion and loss of kidney function in about 15% of cases; this figure is increased with more severe degrees of stenosis. If the progression is gradual, collateral vessels may develop and some function may be preserved. Even if the main arterial supply is lost, the kidney receives some blood supply from capsular blood vessels. These will not support kidney function, but may be sufficient to prevent infarction and loss of kidney structure. Fibromuscular dysplasia does not usually cause complete occlusion of the renal artery, and will usually stabilise once the patient stops growing.
Treatment options are as follows:
medical treatment (antihypertensive therapy, low-dose aspirin and lipid-lowering drugs if appropriate)
angioplasty, with or without mechanical stenting after balloon dilatation
surgical resection of the stenosed segment and reanastomosis.

At present there are no conclusive data to indicate the overall superiority of one approach over another. Angioplasty is widely used, usually with stenting to improve the patency rate. However, there may be substantial risks to these procedures in patients with atherosclerosis-of contrast nephropathy (see Box 14.2, p. 584), of renal artery occlusion and renal infarction, and of atheroemboli (see p. 611) from manipulations in a severely diseased aorta. The overall effect on renal function and on patient survival is far from clear, and trials are currently addressing this. Surgery is now much less commonly undertaken. Conservative medical treatment may be appropriate if there is widespread atheromatous disease of the aorta and elsewhere.
DISEASES OF SMALL INTRARENAL VESSELS
A number of conditions are associated with acute damage and occlusion of small blood vessels (arterioles and capillaries) in the kidney. They are associated to varying degrees with similar changes elsewhere in the body. A common feature of these syndromes is microangiopathic haemolytic anaemia, in which haemolysis occurs as a consequence of damage incurred during passage through the abnormal vessels. Fragmented red cells can be seen on a blood film and are a hallmark of small-vessel disease. The main conditions associated with damage and occlusion of small intrarenal vessels are given in Box 14.19.
Thrombotic microangiopathy
14.19 MICROVASCULAR DISORDERS ASSOCIATED WITH ACUTE RENAL DAMAGE
Thrombotic microangiopathy (haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura)
Associated with verotoxin-producing Escherichia coli
Other (familial, drugs, cancer etc.)
Disseminated intravascular coagulation (see p. 611)
Malignant hypertension
Small-vessel vasculitis (see p. 624)
Systemic sclerosis (scleroderma; see p. 611)
Atheroemboli ('cholesterol' emboli)


Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are types of thrombotic microangiopathy. A common feature of both disorders is damage to endothelial cells of the microcirculation, which is followed by cell swelling, platelet adherence and thrombosis. The aetiology of the syndromes may be rather different, as are the manifestations, although there is substantial overlap. The kidney microcirculation tends to be most affected in HUS, with involvement of other organs (including the brain) in more severe cases. In TTP the brain is commonly affected and involvement of the kidney may be less. Both disorders are characterised by a severe microangiopathy causing a marked reduction in the platelet count and haemoglobin concentration. Other features of intravascular haemolysis-raised bilirubin and lactate dehydrogenase (LDH), decreased haptoglobins-are also present. A reticulocytosis is often seen.
Thrombotic microangiopathy associated with E. coli infection (especially O157 serotypes) is a relatively new condition associated with verotoxin-producing organisms (see p. 42). Although the bacteria live as commensals in the gut of cattle and other domestic livestock, they can cause haemorrhagic diarrhoea in humans when the infection is contracted from contaminated food products, water or other infected individuals. In a proportion of cases, verotoxin produced by the organisms enters the circulation and binds to specific glycolipid receptors that are expressed particularly on the surface of microvascular endothelial cells. In children, this causes diarrhoea-associated (D+)HUS, although in more severe cases the brain and other organs are also affected. D+HUS is now the most common cause of acute renal failure in children in developed countries. In adults, the disease may more closely resemble TTP; both adults and children usually recover, often after 5-15 days of dialysis. No specific treatments have been shown to help.
Other causes of thrombotic microangiopathy have a less certain outlook and are more likely to recur (sometimes after renal transplantation). Familial examples may reflect an abnormality of endothelial cell defence against damage or thrombosis, including complement factor H deficiency, and deficiency of von Willebrand protease (see p. 952). The disease may occur post-partum, in response to certain drugs (especially chemotherapy), after bone marrow transplantation, in malignancy and apparently spontaneously. Plasma exchange using fresh frozen plasma is effective at controlling the disease in many of these examples. There is evidence that it can in some circumstances replace a deficient substance (probably the von Willebrand protease).
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Disseminated intravascular coagulation
In this condition, the most prominent abnormality is consumption of clotting factors due to uncontrolled thrombosis in the microvasculature, leading to severe deficiency of these proteins in the plasma and a tendency to haemorrhage from larger vessels (see p. 952). There may also be thrombocytopenia. Precipitating conditions include septic shock, in which bacterial endotoxin directly activates the coagulation cascade; obstetric complications; disseminated cancer; and other causes of massive internal bleeding or coagulation activation or depletion. Treatment consists of maintaining haemostasis with replacement of clotting factors as required and correcting the underlying condition.
Malignant hypertension
Malignant or accelerated hypertension (see p. 389) is of such severity as to cause acute damage to renal arterioles. It is often symptomatic, with headache, impaired vision and, finally, manifestations of renal failure (see Fig. 14.26). It is usually associated with the features of microangiopathy described above. In the absence of a previous history, it may be difficult to distinguish these patients from those with HUS and marked hypertension. Patients usually respond to effective control of blood pressure, although renal function is permanently lost in 20% of cases.


Figure 14.26 Glomerular capillary thrombosis in malignant hypertension. Similar changes occur in thrombotic microangiopathy. The adjacent arteriole (arrow) shows gross intimal thickening.
Small-vessel vasculitis
Renal disease caused by small-vessel vasculitis is covered on page 624.
Systemic sclerosis (scleroderma)
This connective tissue disease is described on page 1036. Renal involvement is a serious feature, and is characterised by intimal cell proliferation and luminal narrowing of intrarenal arteries and arterioles. Clinically, it usually presents as 'scleroderma renal crisis', with severe hypertension, microangiopathic features and progressive oliguric renal failure. There is intense intrarenal vasospasm, and plasma renin activity is markedly elevated. Use of ACE inhibitors to control the hypertension has improved the 1-year survival from 20% to 75%; however, about 50% of patients continue to require renal replacement therapy.
Atheroembolic renal disease ('cholesterol' emboli)
This is caused by showers of cholesterol-containing microemboli, arising in atheromatous plaques in major arteries. It occurs in patients with widespread atheromatous disease, usually after interventions such as surgery or arteriography. Clinical features are loss of renal function, haematuria and proteinuria, and sometimes eosinophilia and inflammatory features which may mimic a small-vessel vasculitis. Accompanying signs of microvascular occlusion in the lower limbs (e.g. ischaemic toes, livedo reticularis) are common but not invariable (see Fig. 14.27). There is no specific treatment.


Figure 14.27 The foot of a patient who suffered extensive atheroembolism following coronary artery stenting.

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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > GLOMERULAR DISEASES
GLOMERULAR DISEASES
Glomerular diseases may cause any of a characteristic range of abnormalities including haematuria, proteinuria, loss of renal function and hypertension; they continue to be a major source of CRF in developed as well as developing countries (see Fig. 14.10, p. 586). While a few glomerular diseases are inherited, most are acquired. The acquired disorders can be divided into inflammatory/proliferative and non-inflammatory or non-immune types.
INHERITED GLOMERULAR DISEASES
ALPORT'S SYNDROME
A number of uncommon diseases may affect the glomerulus in childhood, but the most important disease affecting adults is Alport's syndrome (see Box 14.20). Most cases arise from a mutation ordeletion of the COL4A5 gene on the X chromosome that results in a progressive degeneration of the GBM (see Fig. 14.28). Some other basement membranes containing the same collagen isoforms are similarly affected, notably in the cochlea.
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Figure 14.28 Alport's syndrome. A Diagrammatic structure of the normal GBM. B The normal GBM (electron micrograph) contains mostly the tissue-specific a3, a4 and a5 chains of type IV collagen. C In Alport's syndrome this network is disrupted and replaced by a1 and a2 chains. Although the GBM appears structurally normal in early life, in time thinning appears, progressing to thickening, splitting and degeneration.
14.20 ALPORT'S SYNDROME
The second most common inherited cause of renal failure (polycystic kidney disease being the most common)
Hallmark is progressive degeneration of GBM (see Fig. 14.28)
Caused by abnormalities of tissue-specific isoforms of type IV (basement membrane) collagen
Associated with sensorineural deafness (to high tones first) and ocular abnormalities
Most cases associated with mutations of COL4A5, encoding a5 (IV) collagen, located at Xq22

X-linked disease (COL4A5)
Affected males progress from haematuria to end-stage renal failure in late teens or twenties
Female carriers usually have haematuria but rarely develop significant renal disease

Autosomal recessive disease (COL4A3, COL4A4)
Females and males equally affected
Carriers may have microscopic haematuria and thin GBM disease


No treatment has been devised to slow the progress of this condition, but patients with Alport's syndrome are good candidates for renal replacement therapy as they are young and usually otherwise healthy. Some of these patients develop an immune response to the normal collagen antigens present in the GBM of a transplanted kidney, and in a small minority anti-GBM disease develops and destroys the allograft.
THIN GBM DISEASE
In 'thin GBM' disease there is glomerular bleeding, usually only at the microscopic or stick-test level, without associated hypertension, proteinuria or reduction of GFR. The glomeruli appear normal by light microscopy, but on electron microscopy the GBM is abnormally thin. The prognosis is good. This autosomal dominant condition accounts for a large proportion of 'benign familial haematuria', and has an excellent prognosis. Some families may be carriers of autosomal recessive Alport's syndrome, but this does not account for all cases.
GLOMERULONEPHRITIS
Although glomerulonephritis literally means 'inflammation of glomeruli', the term is used to include other types of glomerular disease (glomerulopathies) even though there is no histological evidence of inflammation. Glomerular damage may follow a number of insults: immunological injury, inherited error (e.g. Alport's syndrome), metabolic stress (e.g. diabetes mellitus), deposition of extraneous materials (e.g. amyloid), or other direct injury to glomerular cells.
Most glomerulonephritis is presumed to be immunologically mediated. For some diseases there is direct evidence of this-e.g. the anti-GBM antibodies seen in Goodpasture's disease. Deposition of antibody is seen in many types of glomerulonephritis (see Box 14.21). In many, the presumed mechanisms involve cellular immunity, which is more difficult to investigate and prove. The response of several types of glomerulonephritis to immunosuppressive drugs provides further indirect evidence. In most cases the targets of immunity are likely to be glomerular antigens (see Fig. 14.29).
Although deposition of circulating immune complexes was previously thought to be a common mechanism of glomerulonephritis, it now seems likely that most granular deposits of immunoglobulin within glomeruli are caused by 'in situ' formation of immune complexes about glomerular antigens, or about other antigens ('planted' antigens, e.g. viral or bacterial ones) that have localised in glomeruli.
Classifications of glomerulonephritis are largely histopathological and may appear daunting. How these pathological appearances arise is the subject of the next section. The major histopathological types are shown in Box 14.21 and Fig. 14.30, and clinically important examples are described in the text.
Responses to glomerular injury
Glomerular changes that occur following initiation of injury are limited to a small repertoire, and can be simplified to six processes.
Leucocyte infiltration
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Figure 14.29 Cells of the glomerulus and targets of immunity and autoimmunity. The diagram also shows where antibodies and antigen-antibody (immune) complexes may be seen: subepithelial, between podocyte and GBM; intramembranous, within the GBM; subendothelial, between endothelial cell and GBM; and mesangial, within the mesangial matrix (compare with Fig. 14.30).
Generation of chemoattractants and other mediators following injury by immunological or other processes causes endothelial cells to express adhesion molecules to which leucocytes bind. Leucocytes may also migrate towards high concentrations of chemoattractants (chemotaxis), crossing basement membranes by diapedesis. Monocytes can mature into secretory macrophages, which may exacerbate injury; however, monocytes may also play a major role in the resolution of inflammation by phagocytic clearance of apoptotic leucocytes. Current corticosteroid and cytotoxic therapies influence these processes.
Resident cell changes
Hydraulic stress upon mesangial cells, secretory macrophages and recruited platelets may all release mitogens such as platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF). These trigger proliferation of mesangial and endothelial cells and phenotypic change in these and in epithelial cells (podocytes). Such changes lead to alterations in matrix (see below). Resolution involves deletion of excess resident cells by apoptosis and restoration of the resident cell phenotype. Currently available therapies are not known to influence these processes directly, but PDGF and other mediators are potential targets.
Extracellular matrix changes
Secretory macrophages or mesangial cells stressed by (for example) hydraulic stimuli may release transforming growth factor-ß1 (TGF-ß1) that is locally activated. In turn, this fibrogenic cytokine causes mesangial cells to adopt a myofibroblastic phenotype, secreting both matrix components and inhibitors of metalloproteinases (TIMPs), leading to net accumulation of matrix. Similar mechanisms acting on podocytes or endothelial cells may lead to thickening of GBM. Blockade of TGF-ß function is being studied in human disease.
Crescent formation
Severe glomerular capillary injury, most likely mediated by leucocyte-derived reactive oxygen species and injurious proteins, causes breaches in capillary walls. Bleeding into Bowman's space and formation of fibrin clots stimulate the proliferation of parietal epithelial cells of Bowman's capsule. Infiltrating monocytes may join the crescent cells. The resultant crescent may compress capillaries (see Fig. 14.30). Glomerular loss is the rule but resolution may occur in some circumstances (e.g. post-streptococcal nephritis), particularly if Bowman's capsule is not breached. Modification of inflammation using cytotoxic agents and corticosteroids can rescue glomeruli affected by crescents in some other diseases, e.g. systemic vasculitis.
Glomerular capillary thrombosis
Platelet adherence to the glomerular capillary wall may reflect mediator generation within the glomerulus or from the blood, causing endothelial cell activation with adhesion molecule expression, or endothelial cell retraction leading to GBM exposure. Tufts in which glomerular capillaries are occluded usually die by ischaemic necrosis, but resolution is possible, as fibrinolysis can result in recanalisation of capillaries, which can be repaired by angiogenesis. Previous attempts to prevent thrombosis by using anticoagulants in human disease have not proven effective, but angiogenesis could potentially be promoted by therapy.
Glomerulosclerosis
Leucocyte accumulation, resident cell and matrix changes, and recruitment of extraglomerular fibroblasts set up a situation in which progressive and unscheduled apoptosis of resident cells leads to a featureless glomerular scar. This lesion can also arise because of podocyte injury and retraction; naked GBM then adheres to Bowman's capsule, this adhesion enlarges and glomerular filtration occurs directly into the paraglomerular space, causing periglomerular fibrosis, ultimately progressing to a functionless scar.
CRESCENTIC NEPHRITIS (RPGN)
Crescentic nephritis is described on pages 597-598.
MINIMAL CHANGE NEPHROPATHY AND PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
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14.21 GLOMERULONEPHRITIS: TYPES, ASSOCIATIONS AND CAUSES
Histology Immune deposits Pathogenesis Association Clinical features
Minimal change Normal, except on electron microscopy, where fusion of podocyte foot processes is seen (occurs in many types of proteinuria) None Unknown Atopy, HLA-DR7 Drugs Acute and often severe nephrotic syndrome
Good response to corticosteroids
Dominant cause of idiopathic nephrotic syndrome in childhood
Focal segmental glomerulosclerosis (FSGS) Segmental scars in some glomeruli
No acute inflammation
Podocyte foot process fusion seen in primary FSGS with nephrotic syndrome Non-specific trapping in focal scars Unknown; in some, circulating factors increase glomerular permeability Injury to podocytes may be a common feature Healing of previous local glomerular injury HIV infection, heroin misuse, morbid obesity Primary FSGS presents as idiopathic nephrotic syndrome but is less responsive to treatment than minimal change; may progress to renal impairment, can recur after transplantation Secondary FSGS presents with variable proteinuria and outcome
Focal segmental (necrotising) glomerulonephritis Segmental inflammation and/or necrosis in some glomeruli
May be crescent formation Variable according to cause, but typically negative (or 'pauci-immune') Small-vessel vasculitis Primary or secondary small-vessel vasculitis Usually implies presence of systemic disease, and responds to treatment with corticosteroids and cytotoxic agents Check ANCA, ANA
Membranous nephropathy Thickening of GBM Progressing to increased matrix deposition and glomerulosclerosis Granular subepithelial IgG Antibodies to a podocyte surface antigen, with complement-dependent podocyte injury (presumed from animal model) HLA-DR3 (for idiopathic) Drugs Heavy metals Hepatitis B virus Malignancy Usually idiopathic; common cause of adult idiopathic nephrotic syndrome One-third progress; may respond to chlorambucil/prednisolone Associated HLA class II allele varies in different populations
IgA nephropathy Increased mesangial matrix and cells Focal segmental nephritis in acute disease Mesangial IgA Unknown Usually idiopathic Liver disease Very common disease with range of presentations, but usually including haematuria and hypertension (see text)
Mesangiocapillary glomerulonephritis (MCGN) (= membranoproliferative glomerulonephritis, MPGN)
Type I Mesangial cells interpose between endothelium and GBM Subendothelial Deposition of circulating immune complexes or 'planted' antigens Bacterial infection Hepatitis B virus Cryoglobulinaemia (± hepatitis C virus infection) Usually proteinuria, may be haematuria Most common pattern found in association with subacute bacterial infection No proven treatments except where cause can be treated
Type II Mesangial cells interpose between endothelium and GBM Intramembranous dense deposits Associated with complement consumption caused by autoantibodies C3 nephritic factor and partial lipodystrophy Also known as dense deposit disease
Post-infection Diffuse (uniformly in all glomeruli) proliferation of endothelial and mesangial cells
Infiltration by neutrophils and macrophages
May be crescent formation Subendothelial Immune response to streptococcal infection Cross-reactive epitopes or other explanation Streptococcal and other infections Now rare in developed countries Presents with severe sodium and fluid retention, hypertension, haematuria, oliguria Usually resolves spontaneously
Goodpasture's disease (anti-GBM disease) Usually crescentic nephritis Linear IgG along GBM Autoimmunity to a3 chain of type IV collagen HLA-DR15 (previously known as DR2) Associated with lung haemorrhage, but either may occur alone Treat with corticosteroids, cyclophosphamide and plasma exchange to remove circulating autoantibodies
Lupus nephritis Almost any histological type Always positive and often profuse Pattern varies according to type Some anti-DNA antibodies also bind to glomerular targets Complement deficiencies Complement consumption Very variable presentation; sometimes as renal disease alone without systemic features
Responds to cytotoxic therapy in addition to prednisolone

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Figure 14.30 Histopathology of glomerular disease. (A - E light microscopy)
A A normal glomerulus. Note the open capillary loops and thinness of their walls-'should look as if you could cut yourself on them'.
B Focal segmental glomerulosclerosis. The portion of the glomerulus at 2 o'clock shows loss of capillary loops and cells, which are replaced by matrix.
C Focal necrotising glomerulonephritis. The portion of the glomerulus at 6 o'clock is replaced by bright pink material with some 'nuclear dust'. Neutrophils may be seen elsewhere in the glomerulus. There is surrounding interstitial inflammation. Disease of this type is most commonly associated with small-vessel vasculitis (see text) and may progress to crescentic nephritis (see E). D Membranous nephropathy. The capillary loops are thickened (compare with the normal glomerulus) and there is expansion of the mesangial regions by matrix deposition. However, there is no gross cellular proliferation or excess of inflammatory cells. E Crescentic glomerulonephritis. The lower part of Bowman's space is occupied by a semicircular formation ('crescent') of large pale cells, compressing the glomerular tuft. This is usually seen in aggressive inflammatory types of glomerulonephritis.


Figure 14.30 Antibody deposition in the glomerulus. (F - H direct immunofluorescence)
F Granular deposits of IgG along the basement membrane in a subepithelial pattern, typical of membranous nephropathy. G IgA deposits in the mesangium, as seen in IgA nephropathy. H Ribbon-like linear deposits of anti-GBM antibodies along the GBM in Goodpasture's disease. Glomerular structure is well preserved in all of these examples.
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Patients with minimal change nephropathy and a subgroup of patients with FSGS can be seen as opposite ends of a spectrum of conditions causing the idiopathic nephrotic syndrome (see p. 589). Minimal change disease occurs at all ages but accounts for most cases of nephrotic syndrome in childhood and is the underlying diagnosis in about one-quarter of adult patients with nephrotic syndrome. Proteinuria usually remits on high-dose corticosteroid therapy (1 mg/kg prednisolone for 6 weeks), although some patients who respond incompletely or relapse frequently need maintenance corticosteroids, cytotoxic therapy or other agents. Minimal change disease does not progress to renal impairment; the main problems are those of the nephrotic syndrome (see p. 589) and complications of treatment.
FSGS is a histological description (see Fig. 14.30), and similar appearances are found in patients with a number of different causes of renal disease. The primary FSGS group that present with idiopathic nephrotic syndrome and no other cause of renal disease typically show no or a poor response to corticosteroid treatment and often progress to renal failure; the disease frequently recurs after renal transplantation and sometimes proteinuria recurs almost immediately. Cases between these extremes are common. A proportion of patients do show a response to steroids, and other treatments are used as for minimal change disease. As FSGS is a focal process, abnormal glomeruli may not be seen on renal biopsy if only a few are sampled, leading to an initial diagnosis of minimal change nephropathy. Juxtamedullary glomeruli are more likely to be affected in early disease.
In other patients with the histological appearances of FSGS, focal scarring reflects healing of previous focal glomerular injury, such as HUS, cholesterol embolism or vasculitis. In others, it seems to represent particular types of nephropathy-for instance, those associated with heroin misuse, human immunodeficiency virus (HIV) infection and massive obesity. Associations with numerous other forms of injury and renal disorders are reported. There is no specific treatment for most of these.
MEMBRANOUS NEPHROPATHY
This is the most common cause of nephrotic syndrome in adults. A proportion of cases are associated with known causes (see Box 14.21 and Figs 14.30D and F), but most are idiopathic. Of this group, approximately one-third remit spontaneously, one-third remain in a nephrotic state, and one-third show progressive loss of renal function. Short-term treatment with high doses of corticosteroids and alkylating agents may improve both the nephrotic syndrome and the long-term prognosis. However, because of the toxicity of these regimens, most nephrologists reserve such treatment for those with severe nephrotic syndrome or deteriorating renal function.
IgA NEPHROPATHY AND HENOCH-SCHÖNLEIN PURPURA


Figure 14.31 Clinical presentations of IgA nephropathy in relation to age at diagnosis. Henoch-Schönlein purpura is most common in childhood but may occur at any age. Macroscopic haematuria is very uncommon over the age of 40 years. The importance of asymptomatic urine abnormality as the presentation of IgA nephropathy will depend on attitudes to routine urine testing and renal biopsy. It is uncertain whether those presenting with chronic renal impairment have a disease distinct from that of those presenting younger with macroscopic haematuria.
IgA nephropathy is the most commonly recognised type of glomerulonephritis and can present in many ways (see Fig. 14.31). Haematuria is almost universal, proteinuria usual, and hypertension very common. There may be severe proteinuria and nephrotic syndrome, or in some cases progressive loss of renal function. The disease is a common cause of end-stage renal failure. A particular hallmark of the disease in some individuals is acute exacerbations, often with gross haematuria, in association with minor respiratory infections. This may be so acute as to resemble acute post-infectious glomerulonephritis, with fluid retention, hypertension and oliguria with dark or red urine. Characteristically, the latency from clinical infection to nephritis is short-a few days or less. These episodes usually subside spontaneously.
In children, and occasionally in adults, a systemic vasculitis occurring in response to similar infections is called Henoch-Schönlein purpura. A characteristic petechial rash (cutaneous vasculitis) and abdominal pain (gastrointestinal vasculitis) usually dominate the clinical picture, with mild glomerulonephritis being indicated by haematuria. When the disease occurs in older children or adults the glomerulonephritis is usually more prominent. Renal biopsy shows mesangial IgA deposition and appearances indistinguishable from acute IgA nephropathy.
Occasionally, IgA nephropathy progresses rapidly and crescent formation may be seen. The response to immunosuppressive therapy is usually poor. The management of less acute disease is largely directed towards the control of blood pressure in an attempt to prevent or retard progressive renal disease.
ACUTE POST-INFECTIOUS GLOMERULONEPHRITIS
This is most commonly seen following streptococcal infections, but can occur in response to other types. It is much more common in children than adults and is now rarely seen in the developed world. The latency is usually about 10 days after a throat infection, suggesting an immune mechanism rather than direct infection. The latency after skin infection is longer. As for rheumatic fever, only certain streptococcal strains are associated with this complication.
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14.22 CAUSES OF GLOMERULONEPHRITIS ASSOCIATED WITH LOW SERUM COMPLEMENT
Post-infection glomerulonephritis
Subacute bacterial infection-especially endocarditis
SLE
Cryoglobulinaemia
Mesangiocapillary glomerulonephritis-usually type II


An acute nephritis of varying severity occurs with avid sodium retention and oedema, hypertension, reduction of GFR, proteinuria, haematuria and reduced urine volumes. Characteristically, this gives the urine a red or smoky appearance. There are low serum concentrations of C3 and C4 (see Box 14.22) and evidence of streptococcal infection (antistreptolysin O (ASO) titre, culture of throat swab, and other tests if skin infection is suspected).
Renal function begins to improve spontaneously within 10-14 days, and management by fluid and sodium restriction and use of diuretic and hypotensive agents is usually adequate. The renal lesion in almost all children and most adults seems to resolve completely despite the apparent severity of the glomerular inflammation and proliferation seen histologically.
GLOMERULONEPHRITIS ASSOCIATED WITH INFECTION
Bacterial infections, usually subacute (typically subacute bacterial endocarditis), may cause a variety of histological patterns of glomerulonephritis, but usually with plentiful immunoglobulin deposition, and often with evidence of complement consumption (low serum C3; see Box 14.21). In the developed world, hospital-acquired infections are now a common cause of these syndromes. World-wide, glomerulonephritis associated with malaria, hepatitis B, hepatitis C, schistosomiasis, leishmaniasis and other chronic infections is very common. The usual histological patterns are membranous and mesangiocapillary lesions, although many other types may be seen; FSGS associated with HIV infection is increasingly prevalent. Proving a causative relationship between renal disease and infection in individual cases is extremely difficult. Acute and chronic infections may also cause interstitial renal disease (see below).
OTHER GLOMERULAR DISEASES
Some diseases distort glomerular architecture and function by altering the structure or production of normal glomerular components, or by deposition of extraneous materials, without provoking inflammation. Some types of primary glomerulonephritis that do this (minimal change nephropathy, membranous nephropathy) have been discussed above. Almost all the other diseases in which this occurs are haematological or systemic disorders, in which the glomerulus is only one of the structures involved. In the nephropathy of diabetes mellitus (see p. 673) the GBM is thickened and the mesangial matrix expanded, often in a nodular pattern. In amyloidosis (see p. 327) fibrils are deposited in glomeruli and elsewhere. Both amyloidosis and diabetic nephropathy commonly present as nephrotic syndrome.

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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > TUBULO-INTERSTITIAL DISEASES
TUBULO-INTERSTITIAL DISEASES
Tubulo-interstitial disease refers to a heterogeneous group of conditions characterised by structural change and dysfunction of renal tubular structures and the surrounding interstitium. The clinical presentation is often renal failure, either acute and reversible, or chronic; electrolyte abnormalities are commonly observed, especially hyperkalaemia and acidosis. Proteinuria (and albuminuria) is rarely > 1 g/24 hrs but low molecular weight proteinuria is common (e.g. retinol-binding protein, ß2-microglobulin, lysozyme). Haematuria and pyuria are frequent in acute and chronic disease.
Acute tubular necrosis, the most common cause of the clinical syndrome of ARF, is described on page 597. Illustrations of tubulo-interstitial pathology are shown in Figure 14.32.
INTERSTITIAL NEPHRITIS
ACUTE INTERSTITIAL NEPHRITIS
Acute interstitial nephritis (AIN) refers to acute inflammation within the tubulo-interstitium. Precipitating causes include drugs and toxins, and a variety of systemic diseases and infections (see Box 14.23).
Renal biopsies (see Fig. 14.32) show intense inflammation, with polymorphonuclear leucocytes and lymphocytes surrounding tubules and blood vessels, and invading tubules (tubulitis) and occasional eosinophils (especially in drug-induced disease).
14.23 CAUSES OF ACUTE INTERSTITIAL NEPHRITIS
Allergic
Penicillins
NSAIDs
Allopurinol
Many other drugs

Immune
Autoimmune with uveitis or isolated

Infections
Acute bacterial pyelonephritis
Leptospirosis
Tuberculosis
Hantavirus, cytomegalovirus

Toxic
Myeloma light chains
Mushrooms (Cortinarius)


Diagnosis
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Figure 14.32 Tubular histopathology. A Normal tubular histology. The tubules are back-to-back. Brush borders can be seen on the luminal borders of cells in the proximal tubule. B Acute tubular necrosis. There are scattered breaks in tubular basement membranes, swelling and vacuolation of tubular cells, and in places apoptosis and necrosis of tubular cells with shedding of cells into the lumen. During the regenerative phase there is increased tubular mitotic activity. The interstitium is oedematous and infiltrated by inflammatory cells. The glomeruli (not shown) are relatively normal, although there may be endothelial cell swelling and fibrin deposition. C Acute bacterial pyelonephritis. A widespread inflammatory infiltrate that includes many neutrophils is seen. Granulocyte casts are forming within some dilated tubules. Other tubules are scarcely visible because of the extent of the inflammation and damage. D Acute (allergic) interstitial nephritis. In this patient who received an NSAID, an extensive mononuclear cell infiltrate (no neutrophils) involving tubules is seen. This inflammation does not involve the glomeruli (not shown). Sometimes eosinophils are prominent. Transplant rejection looks similar to this.
Less than 30% of patients with drug-induced AIN have a generalised drug hypersensitivity reaction (e.g. fever, rash, eosinophilia), and dipstick testing of the urine is usually unimpressive. However, leucocyturia is common, and eosinophils are to be found in the urine in up to 70% of patients. Deterioration of renal function in drug-induced AIN may be dramatic and resemble RPGN. Careful history, examination and specific tests may point to the diagnosis but renal biopsy is usually required. The degree of chronic inflammation in a biopsy is also a useful predictor of the eventual outcome for renal function. Many patients are not oliguric despite moderately severe ARF, and AIN should always be considered in patients with non-oliguric ARF.
Management
ARF can be managed conservatively (see p. 599); dialysis is only required for symptomatic or ill patients with a blood urea > 30 mmol/l. Many patients with drug-induced AIN recover following withdrawal of the drug alone, but corticosteroids (1 mg/kg/day) accelerate recovery and may prevent long-term scarring. Other specific causes (see Box 14.23) should be treated where possible.
CHRONIC INTERSTITIAL NEPHRITIS
Aetiology
Chronic interstitial nephritis (CIN) is caused by a heterogeneous group of diseases, summarised in Box 14.24. However, it is quite common for the condition to be diagnosed late and for no aetiology to be apparent.
Clinical features
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14.24 CAUSES OF CHRONIC INTERSTITIAL NEPHRITIS
Acute interstitial nephritis
Any of the causes of AIN if persistent
Glomerulonephritis
Varying degrees of interstitial inflammation occur in association with most types of inflammatory glomerulonephritis
Immune/inflammatory
Sarcoidosis
Sjögren's syndrome
SLE, primary autoimmune
Chronic transplant rejection
Toxic
Mushrooms
Lead
Chinese herbs
Balkan nephropathy (see text)
Drugs
All drugs causing AIN
Lithium toxicity
Analgesic nephropathy
Ciclosporin, tacrolimus
Infection
Consequence of severe pyelonephritis
Congenital/developmental
Vesico-ureteric reflux-is associated; causation not clear
Renal dysplasias-often associated with reflux
Inherited-now well recognised but mechanisms unclear
Other-Wilson's disease, medullary sponge kidney, sickle-cell nephropathy
Metabolic and systemic diseases
Hypokalaemia, hypercalciuria, hyperoxaluria
Amyloidosis


Most patients present in adult life with CRF, hypertension and small kidneys. CRF is often moderate (urea < 25 mmol/l) but, because of tubular dysfunction, electrolyte abnormalities are typically more severe (e.g. hyperkalaemia, acidosis). Urinalysis is non-specific. A minority of patients present with hypotension, polyuria and features of sodium and water depletion (e.g. low blood pressure and jugular venous pressure) suggesting severe damage to collecting ducts ('salt-losing nephropathy'). Impairment of urine-concentrating ability and sodium conservation places patients with CIN at risk of superimposed ARF with even moderate salt and water depletion during an acute illness.
The combination of interstitial nephritis and tumours of the collecting system is seen in Balkan nephropathy, so called because of where cases are found, and has been attributed to ingestion of fungal toxins, particularly ochratoxin A, present in food made from stored grain. A plant toxin, aristolochic acid, has been blamed for a rapidly progressive syndrome caused by Chinese herbs. Hyperkalaemia may be disproportionate in CIN or in diabetic nephropathy because of hyporeninaemic hypoaldosteronism (see p. 624). Renal tubular acidosis is seen most often in myeloma, sarcoidosis and amyloidosis.
Management
CRF will require conservative management (see p. 603). A full diagnostic workup for the conditions in Box 14.24 may help to identify a specific drug or toxin which can be withdrawn or suggest a specific diagnosis for treatment. Acidosis can be corrected with oral sodium bicarbonate. Hyperkalaemia will require further measures (see p. 284).
ANALGESIC NEPHROPATHY
Long-term ingestion of analgesic drugs can cause renal papillary necrosis and CIN. In animals, lesions can be induced with almost any NSAID. In humans, mixtures containing aspirin and phenacetin were historically important, and recent surveys show a fall in the incidence of this condition following withdrawal of phenacetin. Dehydration, which reduces medullary blood flow and results in concentration of the drugs in the renal medulla, is probably an important contributory factor.
Clinical features
Patients have usually taken prescribed or over-the-counter analgesic preparations for many years for headaches, backache, rheumatoid arthritis or osteoarthrosis. Asymptomatic disease may be disclosed when abnormalities of blood or urine are found during medical examination. Patients with moderate renal impairment present with malaise, thirst and polyuria due to impaired urinary concentration. Recurrent urinary infection is common. Approximately 60% of patients are hypertensive but 10% may be 'salt-losing'. Renal damage is predominantly tubular; failure to conserve sodium and renal tubular acidosis are common. Acute papillary necrosis is common, and is probably the initial lesion in most cases. Renal colic, ureteric obstruction and acute renal failure may be caused by the passage of fragments of necrotic papillae, which can be recognised by microscopic examination of the urine. ARF may also follow urinary infection or a sudden increase in the intake of analgesics. However, many cases present with established CRF. A recognised complication is the development of carcinoma of the uroepithelium (renal pelvis, ureter or bladder).
Investigations
Apart from the history of drug ingestion, the diagnosis can sometimes be made on the basis of radiological findings and biochemical evidence of tubular dysfunction. The appearance of the papillae on IVU or retrograde pyelography is often diagnostic. The contrast medium appears as a small tract within the papillary substance; later, the papillae may separate, giving rise to a ring shadow. The urine usually contains red cells, and sterile pyuria is common. Proteinuria rarely exceeds 1 g/24 hrs at presentation, but tends to increase as renal failure develops. Renal biopsy shows diffuse interstitial fibrosis and tubular atrophy.
Management
Analgesic preparations must be discontinued; otherwise irreversible renal failure develops. This results in recovery of function in approximately 25% of patients. Treatment also consists of maintaining a fluid intake of 2-3 l/day, treating hypertension and infections, and providing supplements of sodium chloride and sodium bicarbonate to restore ECF volume and correct metabolic acidosis where necessary. Regular follow-up is essential. When renal function is severely impaired, the regimen for management of CRF should be instituted (see p. 603).
SICKLE-CELL NEPHROPATHY
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The longer survival of patients with sickle-cell disease (see p. 926) means that a larger proportion live to develop chronic complications of microvascular occlusion. In the kidney these changes are most pronounced in the medulla, where the vasa recta are the site of sickling because of hypoxia and hypertonicity. Loss of urinary concentrating ability and polyuria are the earliest changes; distal renal tubular acidosis and impaired potassium excretion are typical. Papillary necrosis (as seen in analgesic nephropathy) is very common. A minority of patients develop end-stage renal failure. This is managed according to the usual principles, but response to recombinant erythropoietin is understandably poor. Patients with sickle trait have an increased incidence of unexplained microscopic haematuria, and occasionally overt papillary necrosis.
REFLUX NEPHROPATHY (CHRONIC PYELONEPHRITIS)
This is a chronic interstitial nephritis associated with vesico-ureteric reflux (VUR) in early life, and with the appearance of 'scars' in the kidney, as demonstrated by various imaging techniques. The incidence of reflux nephropathy is not known. About 12% of patients in Europe requiring treatment for end-stage renal disease are said to have renal scarring, but the precise diagnostic criteria are variable.
Pathogenesis
VUR is closely associated with recurrent urinary tract infection (UTI) in childhood, and until recently it was widely assumed that this relationship was critical to the association of VUR with progressive renal damage. However, modern imaging techniques have shown that renal scars can be first seen in utero, in the absence of infection. Furthermore, epidemiological surveys and controlled trials have found that efforts to reduce progression to ESRF by surgical or other means have not been effective.
It is now clear that susceptibility to VUR has a large genetic component, and that it may be associated with renal dysplasia and other abnormalities of the urinary tract. It usually occurs from an apparently normal bladder but it may be associated with outflow obstruction, usually caused by urethral valves. Regardless of other lesions, it is associated with a susceptibility to UTI.
It is clearly true that episodes of severe pyelonephritis may occasionally cause permanent renal damage in adults and children. However, in the absence of other urinary tract abnormalities, acute pyelonephritis in patients over the age of 5 years rarely leads to detectable new scars or renal impairment. Permanent renal damage may occur in association with urinary tract obstruction or other abnormal anatomy (e.g. after renal transplantation). It is not clear that lesser degrees of urine infection are associated with progressive renal damage, though this has not as yet been rigorously disproved.
Reflux diminishes as the child grows, and usually disappears. It is often not demonstrable in an adult with a scarred kidney.
Pathology
The changes, which are not diagnostic, may be unilateral or bilateral and of any grade of severity. Gross scarring of the kidneys, commonly at the poles, is seen with reduced size and narrowing of the cortex and medulla. Renal scars are juxtaposed to dilated calyces. Histologically, there is patchy fibrosis with chronic inflammatory cell infiltration, tubular atrophy, periglomerular fibrosis and eventual disappearance of nephrons. The arteries and arterioles may show sclerosis and narrowing. In patients who develop heavy proteinuria and hypertension, renal biopsies show glomerulomegaly and focal glomerulosclerosis (see p. 616), probably as a secondary change.


Figure 14.33 Vesico-ureteric reflux (grade IV) shown by micturating cystogram. A The bladder has been filled by contrast medium through a urinary catheter. Even before micturition there was gross vesico-ureteric reflux into widely distended ureters and pelvicalyceal systems. B The bladder is now empty except for a small residual pool, but contrast medium is retained in both collecting systems.
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Clinical features
In many cases no symptoms arise directly from the renal lesions, and the patient presents very late with only vague symptoms of renal failure. Discovery of hypertension or proteinuria on routine examination may be the first indication of the disease in individuals with no history of overt UTI. A small proportion of patients with severely scarred kidneys will develop hypertension (sometimes severe) and CRF as teenagers. Symptoms arising from the urinary tract may also be present and include frequency of micturition, dysuria and aching lumbar pain. Occasionally, weakness and fainting result from salt loss in the urine. Pyuria and proteinuria <1 g/24 hrs are common but not invariable. Renal calculi are more common.
A number of women present with hypertension and/or proteinuria in pregnancy. In some patients a positive family history is obtained with an autosomal dominant pattern of inheritance.
Investigations
In mild cases (grades I, II) small amounts of urine pass a short distance up the ureter during voiding, returning to the bladder after cessation of micturition to form residual urine. In severe cases (grades III, IV) reflux occurs up the entire length of the ureter (see Fig. 14.33) and presumably into the renal parenchyma. The IVU shows the diagnostic features. The kidneys are reduced in size and there is localised contraction of the renal substance associated with clubbing of the adjacent calyces (see Fig. 14.34). Culture of the urine is mandatory. Investigations, notably renal ultrasound and radionuclide scanning, are performed to identify any abnormality causing obstruction to the flow of urine. DMSA scans are especially useful to demonstrate scarring (see Fig. 14.9, p. 585). A radionuclide renogram with post-micturition scanning or a micturating cysto-urethrogram will demonstrate VUR. Renal function should be assessed by estimation of the blood urea and creatinine, plasma electrolytes and creatinine clearance.


Figure 14.34 Reflux nephropathy (chronic pyelonephritis). Intravenous urogram revealing clubbing of the calyces which is particularly marked in the upper right pole. The appearances on the left are virtually normal.
Management
If infection is present, it should be treated (see EBM panel) and, if recurrent, preventative measures and prophylactic therapy may be given as described for UTI (see p. 629). If pyonephrosis develops or unilateral renal infection or pain persists, nephrectomy or other measures may be indicated.
The usual principles regarding the management of CRF apply (see p. 603). A salt-losing state may develop in reflux nephropathy and other tubulo-interstitial disorders, and these features should be managed as described on page 604. However, hypertension is common. Rarely, hypertension is cured by the removal of a diseased kidney.
As most childhood reflux tends to disappear spontaneously, and trials have shown small or no benefits from anti-reflux surgery, such intervention is uncommon although it may be considered if there is recurrent pyelonephritis. Local treatments (e.g. the subureteric injection of biocompatible material) are under investigation.
EBM
UTI AND URETERIC REFLUX-medical and surgical management
'Recurrent UTIs are associated with vesico-ureteric reflux and renal scarring or dysplasia. Prophylactic antibiotics reduce recurrences of UTI but there is no evidence for or against their ability to protect against further renal scarring or impairment. There is no evidence that surgery to correct vesico-ureteric reflux reduces UTI or renal scarring, despite their close association.'
Smellie JM, Barrat TM, Gordon I, et al. Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial. Lancet 2001; 357:1329-1333.
Further information: www.clinicalevidence.org

Prognosis
Children and adults with small or unilateral scars have a good prognosis, provided renal growth is normal. With significant unilateral scars there is usually compensatory hypertrophy of the contralateral kidney.
In patients with more severe bilateral disease prognosis correlates with measures of renal function, and with hypertension and proteinuria. If the serum creatinine is normal and hypertension and proteinuria are absent, then the long-term prognosis is usually good.
CYSTIC KIDNEY DISEASES
POLYCYSTIC KIDNEY DISEASE
Infantile polycystic kidney disease is rare; inherited as an autosomal recessive trait, it is associated with hepatic fibrosis and is often fatal in the first year of life due to renal or hepatic failure.
Adult polycystic kidney disease (APKD) is a more common condition and inherited as an autosomal dominant trait. The genetic basis and molecular pathogenesis of this disorder are detailed on page 344.
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Pathology
Small cysts lined by proximal tubular epithelium are present in infancy and enlarge at a variable rate. In fully developed APKD the kidneys are asymmetrically enlarged and contain numerous cysts. These differ in size and are surrounded by a variable amount of parenchyma which often shows extensive fibrosis and arteriolosclerosis.
Clinical features
Affected subjects are usually asymptomatic until later life. After the age of 20 there is often insidious onset of hypertension, which may or may not be associated with deterioration of renal function. Common clinical features are shown in Box 14.25.
Often one or both kidneys can be palpated and the surface may be nodular. Other diseases in which the kidneys may be palpably enlarged are hydronephrosis/pyonephrosis, solitary cyst, compensatory hypertrophy in a single kidney, renal tumours and renal amyloid. The right kidney, and occasionally the lower pole of the left kidney, may be felt on clinical examination in normal slim adults.
About 30% of patients with APKD have hepatic cysts (see Fig. 11.7, p. 344), but disturbance of liver function is rare. Berry aneurysms of cerebral vessels are an associated feature, especially in patients with a family history of this condition, and about 10% of patients have a subarachnoid haemorrhage. Mitral and aortic regurgitation are frequent but rarely severe, and colonic diverticula and abdominal wall hernias are recognised associations. There is a gradual reduction in renal function. However, the mean age of starting dialysis treatment in patients heterozygous for the PKD1 mutation is 52 years; 50% of patients never require dialysis.
14.25 ADULT POLYCYSTIC KIDNEY DISEASE: COMMON CLINICAL FEATURES
Vague discomfort in loin or abdomen due to increasing mass of renal tissue
Acute loin pain or renal colic due to haemorrhage into a cyst
Hypertension
Haematuria (with little or no proteinuria)
Urinary tract infection
Renal failure


Investigations
The diagnosis is made on the basis of clinical findings, family history and ultrasound, which is a sensitive method for demonstrating cysts. Now that the gene defects responsible for APKD have been identified, it is sometimes possible to make a specific genetic diagnosis (see p. 344).
Management
Good control of blood pressure is important, since uncontrolled hypertension accelerates the development of renal failure. Urinary infections must be treated promptly. Patients with impaired ability to conserve sodium ('salt-losing') require supplements of sodium chloride and sodium bicarbonate. The regimen for management of CRF will be needed as renal function deteriorates (see p. 603).
Screening and counselling
See page 351.
CYSTIC DISEASES OF THE RENAL MEDULLA
Cysts predominantly in the renal medulla are found in two different conditions. In medullary sponge kidney (see Fig. 14.35) the cysts are confined to the papillary collecting ducts. The condition is not usually genetic and its aetiology is unknown. Affected patients, usually adults, present with pain, haematuria, stone formation or urinary infection. The diagnosis is made by ultrasound or IVU. Contrast medium is seen to fill dilated or cystic tubules, which are sometimes calcified. The prognosis is generally good.
In medullary cystic diseases (sometimes referred to as nephronophthisis in children) small cortical cysts are also present, and these lead to progressive destruction of the nephron. These conditions, characterised by thirst and polyuria (due to nephrogenic diabetes insipidus), are usually diagnosed in younger patients, and there is often a family history. Sometimes affected patients are 'salt-losing', which aggravates the degree of renal failure. Even when treated appropriately, serious renal failure is usual. The genetic basis of these disorders is complex but gradually becoming clearer.


Figure 14.35 Medullary sponge kidney. Intravenous pyelogram showing contrast medium filling both the collecting system and cavities arising from collecting ducts, especially within papillae of the upper pole. The cavities have been likened to bunches of grapes. A plain abdominal radiograph may show calcification in the same regions.
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Patients with a very long history of renal impairment (usually on long-term dialysis) often develop multiple renal cysts-acquired cystic kidney disease. These are associated with increased erythropoietin production, and sometimes with the development of renal cell carcinoma.
ISOLATED DEFECTS OF TUBULAR FUNCTION
An increasing number of disorders are now known to be due to specific defects of transporter molecules or other functions in renal tubular cells. More emerge regularly, and only a significant few are mentioned here.
Renal glycosuria is a benign defect of tubular reabsorption of glucose and is usually inherited as an autosomal recessive trait. Glucose appears in the urine in the presence of a normal blood glucose concentration.
Cystinuria is a rare condition in which reabsorption of filtered cystine, ornithine, arginine and lysine is defective. The high concentration of cystine in urine leads to cystine stone formation (see p. 632). Other uncommon tubular disorders include vitamin D-resistant rickets, in which reabsorption of filtered phosphate is reduced; nephrogenic diabetes insipidus (see p. 744), in which the tubules are resistant to the effects of vasopressin; and Bartter's and Gitelman's syndromes, in which there is sodium-wasting and hypokalaemia (see p. 287).
The term 'Fanconi's syndrome' is used to describe generalised proximal tubular dysfunction. Notable abnormalities include low blood phosphate and uric acid, the finding of glucose and amino acids in urine, and proximal renal tubular acidosis (see below). In addition to the causes of interstitial nephritis described above, some congenital metabolic disorders are associated with Fanconi's syndrome, notably Wilson's disease, cystinosis and hereditary fructose intolerance.
RENAL TUBULAR ACIDOSIS (RTA)
RTA results from either a defect in reabsorption of bicarbonate in the proximal tubule or a failure of acidification of the urine in the distal tubule. There may be little or no overall reduction in renal function. In both types, gene defects are described; otherwise the causes are diseases affecting the renal interstitium (see Box 14.24, p. 619), or the specific effects of toxins or drugs. Some disorders and toxins predominantly affect the distal tubule and are associated with distal RTA. These include hypercalciuria (see below), hyperoxaluria, amphotericin, solvents, medullary sponge kidney, sickle-cell disease and chronic urinary obstruction.
Distal renal tubular acidosis (classical or type 1)
In this condition the ability to form a very acid urine is lost, and the urine pH cannot be reduced to less than 5.3 even in the presence of severe systemic acidosis. This defect is due to failure of the collecting ducts to secrete hydrogen ions or to sustain the gradient for hydrogen ions between the luminal fluid and the tubular cell. Two types have been described. In complete distal RTA there is persistent hyperchloraemic acidosis. In the incomplete form, the plasma bicarbonate is normal, but the urine pH does not fall to less than 5.3 after ammonium chloride administration. Anorexia and fatigue are common, and there is hypercalciuria, hyperphosphaturia, and consequent stone formation and nephrocalcinosis. Loss of Na+/H+ exchange in collecting ducts leads to loss of sodium in urine and fluid depletion. Osteomalacia develops in part through increased calcium loss. Children present with failure to thrive, polyuria and thirst.
Management consists of determining and dealing with the underlying cause where possible. Bicarbonate supplements should be given in a dose sufficient to keep the plasma bicarbonate in excess of 18 mmol/l. Large doses may be required, starting with a dose of 1 g of sodium bicarbonate 8-hourly and increasing the dose until the desired plasma bicarbonate is achieved and there are no signs of sodium depletion. When hypokalaemia is present, a mixture of sodium and potassium bicarbonate should be given. Initially, about half of the total bicarbonate supplement is given as the potassium salt. The proportion of potassium bicarbonate is determined by regular monitoring of plasma potassium. Patients with osteomalacia may require 1a-hydroxycholecalciferol (alfacalcidol) or calcitriol.
Proximal renal tubular acidosis (type 2)
This may occur as an isolated defect (primary proximal RTA). More commonly, it occurs as part of Fanconi's syndrome (see above). Proximal tubular Na+/H+ exchange is impaired, resulting in decreased bicarbonate reabsorption, large losses of bicarbonate in the urine and a marked reduction in plasma bicarbonate. Once the plasma bicarbonate has fallen to about 12 mmol/l, the reduced filtered load can be reabsorbed by the proximal tubular cells, and the amount of bicarbonate reaching the distal tubule is negligible. In these circumstances, it is possible to show that the collecting duct cells can secrete hydrogen ions against a gradient, so that the urine pH falls to less than 5.3. There is frequently associated hyperchloraemia, potassium depletion and hypocalcaemia. Distinction of proximal and distal RTA requires special tests not considered here.
Any underlying cause should be treated if possible. The plasma bicarbonate should be maintained at a level greater than 18 mmol/l with oral sodium bicarbonate. Very large amounts of bicarbonate are needed, and it is recommended that the starting dose should be 1 mmol/kg daily. A 500 mg sodium bicarbonate capsule provides 6 mmol of bicarbonate. In those patients with hypokalaemia, a proportion of the dose, determined by monitoring plasma potassium, is given as potassium bicarbonate. Where necessary, calcium supplements and 1a-hydroxycholecalciferol are given.

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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > RENAL INVOLVEMENT IN SYSTEMIC DISORDERS
RENAL INVOLVEMENT IN SYSTEMIC DISORDERS
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The kidneys may be directly involved in a number of multisystem diseases or secondarily affected by diseases of other organs. Involvement may be at a pre-renal, glomerular, interstitial or post-renal level. Many of the diseases are described in other sections of this chapter or in other chapters of the book. Diabetes mellitus, systemic vasculitis, SLE, cancer and pregnancy are considered in further detail here.
DIABETES MELLITUS
In patients with diabetes, the steady advance from microalbuminuria to dipstick-positive proteinuria, the development of hypertension and the progression to frank nephrotic syndrome are described on pages 673-674. Not all patients require renal biopsy to establish the diagnosis, but non-diabetic renal disease causes proteinuria in up to 8% of diabetic patients and hence other treatable causes of renal disease should be considered.
Once overt diabetic nephropathy has developed, hypotensive agents reduce the rate of loss of renal function. ACE inhibitors have an effect over and above that caused by reduction of blood pressure, by reducing intraglomerular pressure (see EBM panel, p. 674). Some non-dihydropyridine calcium antagonists have similar effects on proteinuria, and may therefore be useful if ACE inhibitors or angiotensin receptor antagonists cannot be used. Blood pressure-lowering should be aggressive. Beneficial effects have been shown at all levels of blood pressure and multiple agents may be required.


Figure 14.36 The ischaemic hand of a diabetic patient with end-stage renal disease (ESRD). Symptoms and signs were precipitated by formation of an arteriovenous fistula for haemodialysis. The photograph illustrates the difficulties of managing ESRD in diabetic patients.
Management of nephrotic syndrome is according to the usual principles (see p. 589). However, the presence of other diabetic complications often makes the management of nephrotic syndrome and renal impairment more difficult, and fluid retention is often particularly severe. Associated cardiac and peripheral vascular disease and autonomic neuropathy make changes in fluid balance associated with hypoproteinaemia, oedema and renal impairment more difficult to tolerate, and drug side-effects often compound this. Hyperkalaemia may be a prominent feature because of hyporeninaemic hypoaldosteronism, in which reduced renin production from pro-renin and reduced release of aldosterone occur. Volume expansion and atrial natriuretic peptide may contribute to this. Gastroparesis and disordered bowel motility are frequently exacerbated, and irregular intake and absorption of food, plus alterations in the bioavailability of insulin due to a reduction in its elimination and other changes in metabolism that occur as renal function declines, usually lead to a deterioration of blood glucose control. Hypoglycaemic episodes are common in diabetic patients with renal failure. For these reasons, patients with diabetes commonly benefit from commencing renal replacement therapy at an earlier stage than other patients with ESRF, as this permits control of fluid balance and blood pressure with fewer drugs and enables some stabilisation to be achieved. Although the mortality of diabetic patients on dialysis and with renal transplants remains higher than that of other patients and management is often more difficult (see Fig. 14.36), survival rates are improving and their quality of life, especially following renal transplantation, can be good.
SYSTEMIC VASCULITIS
The varieties and classification of systemic vasculitis are considered on page 1040. Renal involvement is most commonly associated with small-vessel vasculitis (SVV), in which capillaritis may profoundly affect glomerular function. This causes an inflammatory glomerulonephritis that is focal in nature; focal necrosis is characteristic (see Box 14.21, p. 614 and Fig. 14.30, p. 615), and often occurs with crescentic changes in the glomeruli. The most important causes of this syndrome, microscopic polyangiitis and Wegener's granulomatosis, are usually associated with antibodies to neutrophil granule enzymes (ANCA, see p. 1043). Vasculitis in other organs may give clues to the underlying systemic disorder and its subtype-e.g. ear, nose and throat involvement and lung disease in Wegener's granulomatosis. The similarity of alveolar and glomerular capillaries means that pulmonary haemorrhage, the consequence of capillaritis affecting alveoli, frequently occurs, together with rapidly progressive glomerulonephritis (see p. 597). In some patients a focal glomerulonephritis with or without crescent formation may occur alone, with ANCA, as a kidney-limited form of systemic vasculitis. Importantly, ANCA have been described in a number of chronic infections associated with renal disease, including endocarditis, HIV and tuberculosis, and hence ANCA alone are not diagnostic of SVV. Inappropriate immunosuppression in these circumstances may be disastrous.
Treatment of the primary types of SVV with cyclophosphamide and corticosteroids is life-saving (see p. 1043). Death from extrarenal manifestations of the disease is prevented, and renal function can be salvaged in acute disease, even if the glomerulonephritis is so severe as to cause oliguria.
Henoch-Schönlein purpura (HSP) and IgA nephropathy are discussed on page 616. HSP is another form of SVV, in which similar focal nephritis is seen by light microscopy. However, instead of being pauci-immune (minimal or no immunoglobulin deposition in the glomeruli), mesangial deposits of IgA are seen, as in IgA nephropathy. ANCA are not usually detected. The disease is usually episodic and self-limiting, but severe progressive renal (or other) disease sometimes justifies the use of immunosuppressive treatment.
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In addition to these common disorders, SVV sometimes occurs in the setting of other systemic inflammatory disorders, and the kidneys may be affected in these. SLE and rheumatoid arthritis are the most common examples of this, although SLE usually involves the kidney in different ways (see below).
Medium- to large-vessel vasculitis (e.g. classical polyarteritis nodosa, p. 1042), in the absence of involvement of small vessels, only causes renal disease when arterial involvement leads to hypertension or renal infarction.
Systemic lupus erythematosus (SLE)
Renal involvement in SLE occurs in approximately 30% of patients within 1 year of diagnosis and a further 20% of patients by 5 years. Although it is clinically silent in many, it usually manifests as glomerulonephritis; serologically, and sometimes clinically, overlapping syndromes (e.g. mixed connective tissue disorder, Sjögren's syndrome) may be associated with interstitial nephritis. As indicated in Box 14.21 (see p. 614), SLE can produce almost any histological pattern of glomerular disease and an accordingly wide range of clinical features ranging from florid RPGN (see p. 597) to chronic nephrotic syndrome.
Most typically, patients present with subacute disease, with inflammatory features (haematuria, hypertension, variable renal impairment) accompanied by heavy proteinuria that often reaches nephrotic levels. In severely affected patients the most common histological pattern is an inflammatory, diffusely proliferative glomerulonephritis with distinct features to suggest lupus. Controlled trials have shown that the risk of ESRF in this type of disease is significantly reduced by cyclophosphamide treatment, often given as regular intravenous pulses (see EBM panel, p. 1036).
Significant renal involvement has traditionally been described as a poor prognostic factor in SLE. It usually signifies a need for more powerful (and therefore more hazardous) immunosuppressive therapy but, in most, renal failure can be prevented. Drug side-effects are important; over-reliance on high doses of corticosteroids to control disease leads to substantial toxicity over many years. Cytotoxic agents carry the predictable risks of bone marrow suppression, infection, infertility and secondary malignancy. The risks of teratogenic effects and loss of fertility are particularly important, as many patients are young women.
Many patients go into relative remission from SLE once ESRF has developed. This may be because ESRF itself is an immunosuppressed state, as indicated by the higher incidence of bacterial infections in ESRF from all causes. Patients with ESRF caused by SLE are usually good candidates for dialysis and transplantation. Although it is one of the diseases that may recur in renal allografts, the immunosuppression required to prevent allograft rejection usually keeps SLE suppressed at the same time.
MALIGNANT DISEASES
Cancer may affect the kidney in many ways (see Box 14.26).
PREGNANCY
14.26 RENAL EFFECTS OF MALIGNANCIES
Direct involvement
Kidney: hypernephroma, lymphoma
Urinary tract: e.g. urothelial tumours, cervical carcinoma
Immune reaction
Glomerulonephritis: especially membranous nephropathy
Systemic vasculitis (rarely): usually ANCA-negative
Metabolic consequences
Hypercalcaemia
Uric acid crystal formation in tubules: usually in tumour lysis syndromes
Remote effects of tumour products
Light chains in myeloma, amyloidosis
Antibodies in cryoglobulinaemia


Pregnancy has important physiological effects on the renal system and is associated with a number of distinct disorders. Physiological adaptations begin in the first few weeks. Peripheral vascular resistance declines, blood volume, cardiac output and GFR increase, and there is usually a reduction in blood pressure and plasma creatinine and urea values in the first trimester. Recordings of blood pressure and urine testing from the first clinic visit are valuable if problems arise later.
14.27 FEATURES AND COMPLICATIONS OF PRE-ECLAMPSIA AND RELATED DISEASES
Clinical syndromes
Eclampsia: severe hypertension, encephalopathy and fits
Disseminated intravascular coagulation
Thrombotic microangiopathy: may also occur post-partum (post-partum HUS)
Acute fatty liver of pregnancy
'HELLP' syndrome: haemolysis, elevated liver enzymes, low platelets (thrombotic microangiopathy with abnormal liver function)
Clinical signs
Hypertension
Proteinuria
Oedema
Other evidence of the clinical syndromes listed above
Investigations
Uric acid levels increased (before renal impairment apparent)
Platelets decreased
Reduced GFR (late)
Fetus small for dates and growing slowly
Fetal distress (late)


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EBM
ASYMPTOMATIC BACTERIURIA-treatment in pregnancy
'There is an increased incidence of pyelonephritis in pregnancy, and asymptomatic bacteriuria predisposes to this and to pre-term delivery. SR of 13 trials including nearly 2500 subjects showed that antibiotic therapy for asymptomatic bacteriuria reduced the incidence of pyelonephritis by 75% and pre-term delivery by 40%. It was not clear how long treatment should be continued or how frequently further screening should be undertaken.'
Smail F. Antibiotics for asymptomatic bacteriuria in pregnancy (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk

Some conditions are more common in pregnancy, the manifestations of others are modified by the physiological changes of pregnancy, and a few diseases are unique to pregnancy (see Box 14.27). Pyelonephritis is more common, perhaps because of dilatation of the urinary collecting system and ureters. Asymptomatic bacteriuria should be treated in pregnancy (see EBM panel). Proteinuria caused by glomerular disease is always exacerbated, and nephrotic syndrome may develop without any alteration in the underlying disease in individuals who had only slight proteinuria before pregnancy. This gives a particular risk of venous thromboembolism, which is now the leading cause of maternal deaths in developed countries.
Systemic autoimmune diseases are typically relatively quiescent during pregnancy, but tend to relapse in the first few weeks and months following delivery. Patients with such diseases who may become pregnant should be aware of the extra associated risks. Drugs used should be safe in pregnancy wherever possible. During pregnancy, therapy should not usually be stopped, but blood pressure targets may be modified (after discussion with the patient) and agents altered to those of proven safety.
Pre-existing renal disease increases the fetal and maternal risk involved in pregnancy, to a degree dependent on the level of renal function, proteinuria and hypertension. Similar consideration should be given to counselling and therapy.
Pre-eclampsia and related disorders
Pre-eclampsia is a systemic disorder that occurs in or near the third trimester of pregnancy. Its aetiology is unknown, although a number of risk factors are described (see Box 14.28).
14.28 RISK FACTORS FOR PRE-ECLAMPSIA
First pregnancy
First pregnancy with a new partner
Pre-eclampsia in previous pregnancies
Age <> 35 years
Multiple pregnancy (singleton < twin < triplets etc.)
Pre-existing hypertension
Pre-existing renal disease


Pre-eclampsia is traditionally defined by the triad of oedema, proteinuria and hypertension. However, oedema is common in late pregnancy, proteinuria is a late sign and, while hypertension is usually present, it may be relative, mild, or even absent in certain variants of pre-eclampsia. Furthermore, all these features occur in renal disease that may be exacerbated by pregnancy. Differentiating the two may be important, as pre-eclampsia is a progressive disease presenting increasing risk to the fetus and the mother, whereas in renal disease continuing the pregnancy may permit delivery of a healthier, more mature baby. Proteinuria and hypertension in the early part of pregnancy suggest pre-existing renal disease.
The only effective management for pre-eclampsia is delivery. The role of antiplatelet therapy remains controversial (see first EBM panel). Hypertension is a consequence not the cause of the disorder, and treatment is only justified to lower it from severe and immediately dangerous levels (e.g. higher than 180/110). Treating lower levels has been shown to confer no benefit, and exposes the fetus to additional drugs. If life-threatening complications are not present and the baby is immature, corticosteroids may be given to induce maturation of fetal lungs, and delivery postponed while mother and baby are closely observed. Magnesium sulphate has been shown to reduce the incidence of eclamptic convulsions (see second EBM panel).
EBM
PREVENTION OF PRE-ECLAMPSIA-role of antiplatelet therapy
'SR of several RCTs involving over 32 000 women with medium- and high-risk pregnancies concluded that the use of low-dose aspirin results in a small (15%) reduction in pre-eclampsia, and a similar reduction in perinatal mortality (14%) and delivery before 37 weeks (8%). However, the single largest RCT included failed to detect any beneficial effect on proteinuric pre-eclampsia or perinatal death. It remains to be determined which women benefit most from aspirin, when treatment should be started, and what is the optimum dose.'
Duley L, Henderson-Smart D, Knight M, King JF. Antiplatelet agents for prevention of pre-eclampsia and its consequences: systematic review. BMJ 2001; 322:329-333.
Further information: www.cochrane.co.uk

EBM
ECLAMPSIA-role of magnesium sulphate
'SR of four RCTs demonstrates that magnesium sulphate (4 g loading dose followed by 1 g/hour infusion) was substantially more effective than phenytoin or diazepam for the treatment of eclamptic convulsions.'
Which anticonvulsant for women with eclampsia? Evidence from Collaborative Eclampsia Trial. Lancet 1995; 345:1455-1463.
Duley L, Henderson-Smart D. Magnesium sulphate versus phenytoin for eclampsia (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk

Acute renal failure may occur in the setting of most of these syndromes. Cortical necrosis (irreversible infarction of the renal cortex) is more likely to occur in pregnancy as a complication of some of these disorders.

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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > DRUGS AND THE KIDNEY
DRUGS AND THE KIDNEY
PRESCRIBING IN RENAL DISEASE
Many drugs and drug metabolites are excreted by the kidney. The presence of renal impairment alters the required dose and frequency of those which are affected. This is discussed on page 154.
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DRUG-INDUCED RENAL DISEASE
The susceptibility of the kidney to damage by drugs stems from the fact that it is the route of excretion of many water-soluble compounds, including drugs and their metabolites. Some may reach high concentrations in the renal cortex as a result of proximal tubular transport mechanisms. Others are concentrated in the medulla by the operation of the counter-current system. The same applies to certain toxins.
Toxic renal damage may occur by a variety of mechanisms (see Box 14.29). Very commonly, drugs contribute as one of multiple insults to the development of acute tubular necrosis. Haemodynamic renal impairment, acute tubular necrosis, and allergic reactions if recognised early enough are usually reversible. However, other types, especially those associated with extensive fibrosis, are less likely to be reversible. Numerically, reactions to NSAIDs and ACE inhibitors are the most important.
14.29 MECHANISMS AND EXAMPLES OF DRUG- AND TOXIN-INDUCED RENAL DISEASE/DYSFUNCTION
Mechanism Drug or toxin Comments
Haemodynamic NSAIDs Especially as a cofactor. Via inhibition of prostaglandin synthesis
ACE inhibitors Reduce efferent glomerular arteriolar tone. Toxic in the presence of renal artery stenosis and other conditions of renal hypoperfusion
Radiographic contrast media Effect mediated via intense vasoconstriction, but this may not be the primary effect of these drugs
Acute tubular necrosis Aminoglycosides, amphotericin In most examples there is evidence of direct tubular toxicity, but haemodynamic and other factors probably contribute
Paracetamol May occur with or without serious hepatotoxicity
Others Drugs often act as one of several cofactors
Radiographic contrast media May be secondary to precipitation in tubules.
Furosemide (frusemide) is a cofactor
Loss of tubular/collecting duct function Lithium
Cisplatin Dose-related, partially reversible loss of concentrating ability
Aminoglycosides, amphotericin At lower exposures than cause ATN
Immune (glomerular) Penicillamine, gold Membranous nephropathy
Mercury and heavy metals Membranous nephropathy
Penicillamine Crescentic or focal necrotising glomerulonephritis in association with ANCA and systemic small-vessel vasculitis
NSAIDs Minimal change nephropathy
Immune (interstitial) NSAIDs, penicillins, many others Acute interstitial nephritis
Chronic interstitial nephritis (alone) Lithium
Ciclosporin, tacrolimus As a consequence of acute toxicity. Otherwise controversial
The major problem with these drugs
Lead, cadmium Consequence of chronic toxicity
Bence Jones protein Only some light chains are nephrotoxic
Ochratoxin and other fungal toxins Produced by Aspergillus species. Putative cause of Balkan nephropathy (see p. 619)
Aristolochic acid and other plant toxins Found in Aristolochia clematis. Putative cause of 'Chinese herb' nephropathy
Chronic interstitial nephritis (with papillary necrosis) Various analgesics (See p. 618)
Obstruction (crystal formation) Aciclovir Crystals of the drug form in tubules. Aciclovir is now more common than the original example of sulphonamides
Chemotherapy Uric acid crystals forming as a consequence of tumour lysis (typically a first-dose effect in haematological malignancy)
Retroperitoneal fibrosis Methysergide*, practolol* Idiopathic is more common (see p. 592)

*These drugs are no longer in use in the UK.
Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs have the predictable effect of impairing renal function in individuals where compensatory mechanisms are maintaining renal function (e.g. heart failure, cirrhosis, sepsis and renal impairment of almost any type), and may precipitate acute tubular necrosis in susceptible patients. This is a class effect that is related to alteration of essential prostaglandin-mediated vasodilatation. In addition, idiosyncratic immune reactions may occur: minimal change nephrotic syndrome and acute interstitial nephritis (see p. 617)-and these may occur together. Analgesic nephropathy (see p. 619) is an occasional complication of long-term use.
Angiotensin-converting enzyme (ACE) inhibitors
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ACE inhibitors abolish the compensatory angiotensin II-mediated vasoconstriction of the glomerular efferent arteriole that occurs to maintain glomerular perfusion pressure distal to a renal artery stenosis (see Fig. 14.1, p. 579). If the stenosis is bilateral, or occurs in a single functioning kidney, an acute deterioration in renal function occurs. These drugs are increasingly used in patient groups at high risk of atherosclerotic renal artery stenosis, so the reaction is common, and monitoring of renal function before and after initiation of therapy is essential.

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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > INFECTIONS OF THE KIDNEY AND URINARY TRACT
INFECTIONS OF THE KIDNEY AND URINARY TRACT
INFECTIONS OF THE LOWER URINARY TRACT
When the urinary tract is anatomically and physiologically normal, and local and systemic defence mechanisms are intact, bacteria are confined to the lower end of the urethra. Urinary tract infection (UTI) implies multiplication of organisms in the urinary tract.
It is usually associated with the presence of more than 100 000 organisms/ml in a midstream sample of urine (MSU). However, contamination can also lead to high bacterial counts, which should therefore be interpreted with caution in the absence of pyuria. Such infections are much more common in women, about one-third of whom have a UTI at some time. The prevalence of UTI in women is about 3% at the age of 20, increasing by about 1% in each subsequent decade. In males UTI is uncommon except in the first year of life and in men over 60, in whom a degree of urinary tract obstruction due to prostatic hypertrophy is common. UTI causes considerable morbidity and, in a small minority of cases, renal damage and chronic renal failure.
Pathogenesis
UTI may be uncomplicated or complicated (see Box 14.30). Complicated infections may result in permanent renal damage, whereas uncomplicated infections rarely (if ever) do so. Uncomplicated infections are almost invariably due to a single strain of organism.
14.30 PATHOGENESIS OF URINARY TRACT INFECTION
Uncomplicated
Anatomically and physiologically normal urinary tract
Normal renal function
No associated disorder which impairs defence mechanisms
Complicated
Abnormal urinary tract, e.g. obstruction, calculi, vesico-ureteric reflux, neurological abnormality, in-dwelling catheter, chronic prostatitis, cystic kidney, analgesic nephropathy, renal scarring
Associated disorder or treatment that predisposes to UTI (e.g. diabetes mellitus)


Outside hospitals, E. coli derived from the faecal reservoir accounts for about 75% of infections, the remainder being due to Proteus,Pseudomonas species, streptococci or Staphylococcus epidermidis. In hospital a greater proportion of infections are due to organisms such as Klebsiella or streptococci, but faecal E. coli still predominates. Certain strains of E. coli have a particular propensity to invade the urinary tract.
The first stage in the development of UTI is colonisation of the periurethral zone with pathogenic, usually faecal, organisms. The urothelium of susceptible persons may have more receptors to which virulent strains of E. coli become adherent. In women, the ascent of organisms into the bladder is facilitated by the short urethra and absence of bactericidal prostatic secretions. Sexual intercourse causes minor urethral trauma and may transfer bacteria from the perineum into the bladder. Instrumentation of the bladder may also introduce organisms. Multiplication of organisms then depends on a number of factors, including the size of the inoculum and virulence of the bacteria.
Residual urine left after voiding increases the potential for bacterial multiplication; thus, patients with bladder outflow obstruction, gynaecological abnormalities, pelvic floor weakness or neurological problems are susceptible to infection. In those with vesico-ureteric reflux (see p. 620) urine expelled into the ureters during voiding returns to the bladder when it relaxes, again leading to incomplete voiding. Injury to the mucosa and the presence of a foreign body in the bladder also increase the risk of infection.
Clinical features
The varying clinical presentation of UTI is outlined in Box 14.31. There is often an abrupt onset of frequency of micturition and dysuria. Scalding pain is felt in the urethra during micturition. Cystitis may give rise to suprapubic pain during and after voiding. After the bladder has been emptied, there may be an intense desire to pass more urine due to spasm of the inflamed bladder wall. Systemic symptoms are usually slight or absent. Suprapubic tenderness is often present. The urine may have an unpleasant odour and appear cloudy. Gross haematuria may occur. The diagnosis depends on:
the characteristic clinical features
demonstration of a significant growth of organisms in an MSU (see Box 14.34)
the presence of neutrophils in the urine (pyuria).

14.31 CLINICAL PRESENTATION OF URINARY TRACT INFECTION
Asymptomatic bacteriuria
Symptomatic acute urethritis and cystitis
Acute prostatitis
Acute pyelonephritis
Septicaemia (usually Gram-negative bacteria)


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14.32 ANTIBIOTIC REGIMENS FOR TREATMENT OF URINARY TRACT INFECTIONS IN ADULTS
Treatment of presumed urinary tract infection Treatment of presumed pyelonephritis Treatment of acute prostatitis Prophylactic or suppressive therapy
Drug Dose Duration of course Dose Duration of course Dose Duration of course Dose
Trimethoprim 300 mg daily 3 days 300 mg daily 7-14 days 200 mg 12-hourly 4-6 weeks 100 mg/night
Co-amoxiclav 250 mg 3 days 250-500 mg 7-14 days 250 mg/night
8-hourly 8-hourly
Gentamicin1 3-5 mg/kg i.v. daily1 7-14 days
Cefuroxime2 250 mg 12-hourly
oral or 750 mg
6-8-hourly i.v. 7-14 days
Start treatment i.v. in
seriously ill patient
Ciprofloxacin2 250-500 mg
12-hourly 3 days 250-500 mg
12-hourly oral or
100 mg 12-hourly i.v. 7-14 days 250 mg 12-hourly 4-6 weeks
Cefalexin 250 mg/night
Erythromycin 250 mg 6-hourly 4-6 weeks

1Dose determined by plasma [creatinine] and [gentamicin].
2Modification of dosage is necessary when renal function is severely impaired.
The presence of neutrophils is almost invariable in symptomatic infections, but is not universal. The number of organisms amounting to a 'significant' culture is based on probabilities. Urine taken by a sterile technique from a ureter or by suprapubic aspiration should be sterile, so the presence of any organisms is significant. In the presence of symptoms and pyuria, a small number of organisms is significant. In asymptomatic patients, more than 105/ml organisms is usually taken as significant (covert bacteriuria, see below).
Management
A fluid intake of at least 2 l/day is helpful. Box 14.32 shows recommended antibiotic regimens for the treatment of UTI in adults. Ideally, results of urine culture and sensitivities should be available before treatment, but if the patient is in discomfort treatment may be started while awaiting the result. Ampicillin and amoxicillin are no longer the drugs of choice for empirical treatment because of the widespread emergence of resistance among E.coli. Trimethoprim is still useful in domiciliary practice although resistant organisms are being encountered with increasing frequency. Nitrofurantoin or co-amoxiclav remain effective in terms of bacterial sensitivity, but nitrofurantoin should not be used for pyelonephritis because of its poor serum and tissue levels. Penicillins and cephalosporins are safe to use in pregnancy but trimethoprim, sulphonamides, quinolones and tetracyclines should be avoided.
Failure to eradicate an organism suggests that one of the complicating factors listed above is present. Investigations should be performed to diagnose the underlying problem, which should be treated appropriately. Failing this, after a further course of antibiotics, suppressive antibiotic therapy can be used to prevent recurrent symptoms, septicaemia and renal damage as outlined in Box 14.32. Urine is cultured regularly and the antibiotic changed as required.
14.33 PROPHYLACTIC MEASURES TO BE ADOPTED BY WOMEN WITH RECURRENT URINARY INFECTIONS
Fluid intake of at least 2 l/day
Regular emptying of bladder (3-hour intervals by day and before sleep)
Complete emptying of bladder
Double micturition if reflux present (The patient should be advised, particularly before retiring for the night, to empty the bladder and then attempt to empty the bladder a second time approximately 10-15 minutes later)
Emptying bladder before and after intercourse
The above regimen is started after completion of a curative course of treatment and continued for several months.

Reinfection with another organism, or with the same organism after an interval, is not uncommon, particularly in sexually active women. Simple measures may prevent recurrence (see Box 14.33). If these fail, freedom from attacks may be achieved by taking a single nightly dose of a suitable antibiotic after voiding and before going to bed, as above.
All individuals with signs of pyelonephritis or systemic infection must be more fully investigated, as shown in Box 14.34. Men and children with recurrent simple infections should also be investigated. In women, recurrent infections are so common that this is only justified if infections are frequent or severe.
COVERT OR ASYMPTOMATIC BACTERIURIA
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14.34 INVESTIGATION OF PATIENTS WITH ACUTE URINARY TRACT INFECTION
Investigation Indications
Culture of MSU or urine obtained by suprapubic aspiration All patients
Microscopic examination of urine for white cells, red cells and casts All patients
Dipstick examination of urine for blood, protein and glucose All patients
Full blood count Infants; children; adults with acute pyelonephritis or prostatitis
Plasma urea, electrolytes, creatinine Infants; children; acute pyelonephritis; recurrent UTI
Blood culture Fever, rigors or evidence of septic shock
Pelvic examination Women with recurrent UTI
Rectal examination Men (to examine prostate)
Renal ultrasonography To identify obstruction, cysts, calculi Infants, children, men after single UTI, and women who have (1) acute pyelonephritis; (2) recurrent UTI after urinary tract treatment; (3) had UTI or covert bacteriuria in pregnancy (IVU 6 weeks after delivery)
Intravenous urography (IVU) including film of bladder after voiding, to identify physiological and anatomical abnormalities Alternative to ultrasound, particularly to image collecting system and ureter
Micturating cysto-urethrography (MCU) to identify and quantitate vesico-ureteric reflux and disturbed bladder emptying Infants; children with abnormal IVU; any patient thought to have a disturbance of bladder emptying
Cystoscopy Patients with chronic haematuria; patients with a suspected bladder lesion

This is defined as more than 105/ml organisms in the MSU of apparently healthy asymptomatic patients. Approximately 1% of children under the age of 1, 1% of schoolgirls, 0.03% of schoolboys and men, 3% of non-pregnant adult women and 5% of pregnant women have covert bacteriuria. There is no evidence that this condition causes chronic renal scarring in non-pregnant adults with normal urinary tracts. When it occurs in infants or in pregnant women, treatment is required, and subsequent investigation may be indicated. In the presence of urinary tract abnormalities, covert bacteriuria may again be more significant and require intervention.
URETHRAL SYNDROME
Some patients, usually female, have symptoms suggestive of urethritis and cystitis but no bacteria are cultured from the urine. Possible explanations include infection with organisms not readily cultured by ordinary methods (e.g. Chlamydia, certain anaerobes), irritation by or allergy to toilet preparations or disinfectants, symptoms related to sexual intercourse, or post-menopausal atrophic vaginitis. Antibiotics are not indicated.
CATHETER-RELATED BACTERIURIA
In hospital patients catheter-related bacteriuria increases the risk of Gram-negative bacteraemia by a factor of five. However, bacteriuria becomes almost universal after 30 days of catheterisation, and should not be treated in asymptomatic patients as it promotes the emergence of antibiotic resistance. Prevention is all-important and depends on sterile insertion, closed drainage systems and prompt catheter removal when not required.
ACUTE PROSTATITIS
This is often accompanied by perineal pain and considerable systemic disturbance. The prostate is usually very tender. The diagnosis is confirmed by a positive culture from urine or from urethral discharge obtained after prostatic massage. The treatment of choice is trimethoprim or erythromycin, which penetrates prostatic secretions. A 4-6-week course is required (see Box 14.32).
INFECTIONS OF THE UPPER URINARY TRACT AND KIDNEY
The proportion of patients with cystitis or bacteriuria in whom the kidney is involved is unknown, but a figure of 50% has been suggested. Clinically, it is often impossible to know if renal infection is present.
Pathogenesis
Bacterial infection of the renal parenchyma is usually due to ascent of organisms via the ureter, although it can be blood-borne. About 75% of infections are due to E. coli, the remainder to Proteus species, Klebsiella, staphylococci or streptococci. One or more complicating factors are commonly present (see Box 14.30) but in infants and women infection can occur in the absence of such factors. Stasis within the urinary tract compromises its defences. Renal cysts or scars facilitate infection. The renal medulla may be particularly susceptible to infection because the low oxygen tension, high osmolality and high concentrations of H+ and ammonia interfere with the function of leucocytes. The high osmolality probably favours conversion of bacteria to antibiotic-resistant L-forms.
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ACUTE PYELONEPHRITIS
Pathology
The renal pelvis is inflamed and small abscesses are often evident in the renal parenchyma. Histological examination shows focal infiltration by neutrophils, which can often be seen within the tubules. These cells are uncommon in other pathological conditions.
Clinical features
There is sudden onset of pain in one or both loins, radiating to the iliac fossae and suprapubic area. About 30% of patients have dysuria due to associated cystitis. Features suggesting renal infection may be absent, particularly in the elderly. Fever is usually present, and rigors and vomiting may occur. Septicaemia with hypotension may supervene. Tenderness and guarding are usually present in the lumbar region. There is a leucocytosis. Examination of urine reveals pyuria, organisms, red cells and tubular epithelial cells.
Acute pyelonephritis in infants and children may present as fever without localising symptoms. The initial feature may be a convulsion; apathy, abdominal distension and diarrhoea may occur. In a febrile child, the urine should always be examined for pus cells and organisms.
Rarely, acute papillary necrosis follows an attack of acute pyelonephritis. Fragments of renal papillae are excreted in the urine and can be identified histologically. This complication, which may lead to acute renal failure, is particularly liable to occur in patients with diabetes mellitus or chronic urinary obstruction. It is also seen (in the absence of infection) in analgesic nephropathy and sickle-cell disease.
Differential diagnosis
Acute pyelonephritis should be distinguished from acute appendicitis, diverticulitis, cholecystitis and salpingitis, and also from perinephric abscess. In this condition there is marked pain and tenderness in the renal region, and often bulging of the loin on the affected side. Patients are extremely ill, with fever, leucocytosis and positive blood cultures. Urinary symptoms are absent, and the urine contains neither pus cells nor organisms.
EBM
PYELONEPHRITIS IN NON-PREGNANT WOMEN-optimum antibiotic regimens
'RCTs have consistently found that oral antibiotic treatment with trimethoprim-sulfamethoxazole, amoxicillin-clavulanic acid or a fluoroquinolone is effective in female outpatients with uncomplicated infection.'
'There is limited evidence that intravenous antibiotics are effective in women admitted to hospital with uncomplicated infection, and that ampicillin should not be used alone to treat infection with E. coli because of antimicrobial resistance.'
'Two RCTs of oral versus intravenous antibiotics found no significant difference in effectiveness.'
Cooper B, Chew L, Fihn S. Pyelonephritis in non-pregnant women. Clinical Evidence 2000; 3:955-960.
Pinson AG, Philbrick JT, Lindbeck GH, Schorling JB. Oral antibiotic therapy for acute pyelonephritis: a methodologic review of the literature. J Gen Intern Med 1992; 7:544-553.
Further information: www.clinicalevidence.org

Management
Box 14.34 outlines the necessary investigations. Diagnosis depends on the clinical features and results of urine culture. Renal tract ultrasound should be performed without delay. Severe cases require intravenous antibiotic therapy (e.g. with a cephalosporin or gentamicin; see Box 14.32 and EBM panel), later switching to an appropriate oral agent. In less severe cases oral antibiotics can be used throughout. Penicillins and cephalosporins are safe in pregnancy; other antibiotics should usually be avoided. Treatment should be given for 7-14 days. Urine culture should be repeated during the course of antibiotics, and 7 and 21 days after treatment.
RENAL TUBERCULOSIS
Tuberculosis of the kidney is invariably secondary to tuberculosis elsewhere (see p. 532) and occurs as a result of blood-borne infection. The initial lesion develops in the renal cortex and, if untreated, may ulcerate into the pelvis, with consequent involvement of the bladder, epididymis, seminal vesicles and prostate. The disease tends to occur in young people, and may present with recurrent haematuria and dysuria due to secondary involvement of the bladder. In addition, the general features of tuberculosis, i.e. malaise, fever, lassitude and weight loss, may be present. Chronic renal failure may result from destruction of kidney tissue, or be due to obstruction of the urinary tract when lesions heal by fibrosis. Culture of the urine by ordinary methods may be sterile in spite of pyuria, and indeed sterile pyuria is an indication to perform special cultures for tubercle bacilli. The extent of the infection with regard to the lower urinary tract should be ascertained by cystoscopic examination.
ISSUES IN OLDER PEOPLE
URINARY INFECTION
The prevalence of asymptomatic bacteriuria rises with age; amongst the frailest in institutional care it rises to approximately 40% in women and 30% in men.
Factors contributing to this may include an increased prevalence of underlying structural abnormalities, post-menopausal oestrogen deficiency and increased residual urine (in women), and prostatic hypertrophy with reduced bactericidal activity of prostatic secretions (in men).
The urinary tract is the most frequent source of bacteraemia in older patients admitted to hospital.
New or increased incontinence is a common presentation of urinary tract infection in older women.
There is no evidence that urinary infection in old age presents with subtle changes in mental state or function, without clinical findings localised to the urinary tract.
Post-menopausal women with acute lower urinary tract symptoms have a relatively poorer response to short courses of antibiotics, and may require longer than 3 days' therapy.
There is little evidence for the benefit of treating asymptomatic bacteriuria in old age; it does not improve symptoms of chronic incontinence, nor does it decrease episodes of morbidity from symptomatic urinary infection or mortality.
Treatment of asymptomatic bacteriuria may simply lead to adverse effects from the antibiotic and promote the emergence of resistant organisms.



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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > URINARY TRACT CALCULI AND NEPHROCALCINOSIS
URINARY TRACT CALCULI AND NEPHROCALCINOSIS
Aetiology
Urinary calculi consist of aggregates of crystals containing small amounts of proteins and glycoprotein. Different types occur with different frequencies in different parts of the world, probably as a consequence of dietary and environmental factors, but genetic factors may also make a significant contribution. In Europe, renal stones in which the crystalline component consists of calcium oxalate are the most common, and stones containing calcium as oxalate, phosphate or both comprise about 80% of the total. About 15% contain magnesium ammonium phosphate (struvite; these are often associated with infection), and small numbers of pure cystine or uric acid stones are found. Rarely, drugs may form stones (e.g. indinavir, ephedrine).
In developing countries, bladder stones are common, particularly in children. In developed countries the incidence of childhood bladder stones is low, and renal stones in adults are more common. In a North American survey, 12% of men and 5% of women had experienced a renal stone by the age of 70 years. It is surprising that stones and nephrocalcinosis are not more common, since some of the constituents are present in urine in concentrations which exceed their maximum solubility in water. However, urine contains proteins, glycosaminoglycans, pyrophosphate and citrate which may help to keep otherwise insoluble salts in solution.
A number of risk factors and predisposing conditions are known for renal stone formation (see Box 14.35). However, in developed countries most calculi occur in healthy young men in whom investigations reveal no clear single predisposing cause.
14.35 KIDNEY STONES: PREDISPOSING FACTORS AND CONDITIONS
Environmental and dietary
Low urine volumes: high ambient temperatures, low fluid intake
Diet: high protein intake, high sodium, low calcium
High sodium excretion
High oxalate excretion
High urate excretion
Low citrate excretion

Other medical conditions
Hypercalcaemia of any cause (see p. 715)
Ileal disease or resection (leads to increased oxalate absorption and urinary excretion)
Renal tubular acidosis type I (distal) (e.g. in Sjögren's syndrome)

Congenital and inherited conditions
Familial hypercalciuria
Medullary sponge kidney
Cystinuria
Renal tubular acidosis type I (distal)
Primary hyperoxaluria




Figure 14.37 Bilateral staghorn calculi. The intravenous pyelogram demonstrates that, while some dye is being excreted by the right kidney, there is little function on the left.
Pathology
Urinary concretions vary greatly in size. There may be particles like sand anywhere in the urinary tract, or large round stones in the bladder. Staghorn calculi fill the whole renal pelvis and branch into the calyces (see Fig. 14.37); they are usually associated with infection and composed largely of struvite. Deposits of calcium may be present throughout the renal parenchyma, giving rise to nephrocalcinosis. This is especially liable to occur in patients with renal tubular acidosis, hyperparathyroidism, vitamin D intoxication and healed renal tuberculosis.
Clinical features
These vary according to the size, shape and position of the stone, and the nature of any underlying condition. Renal calculi or nephrocalcinosis may be present for years without giving rise to symptoms, and may be discovered during radiological examination for another disorder. More commonly, patients present with pain, recurrent urinary infection or clinical features of urinary tract obstruction. Protein, red cells or leucocytes may appear in the urine.
When a stone becomes impacted in the ureter, an attack of renal colic develops. The patient is suddenly aware of pain in the loin, which radiates round the flank to the groin and often into the testis or labium, in the sensory distribution of the first lumbar nerve. The pain steadily increases in intensity to reach a maximum in a few minutes. The patient is restless, and generally tries unsuccessfully to obtain relief by changing position or pacing the room. There is pallor, sweating and often vomiting, and the patient may groan in agony. Frequency, dysuria and haematuria may occur. The intense pain usually subsides within 2 hours, but may continue unabated for hours or days. The pain is usually constant during attacks, though slight fluctuations in severity may occur. Contrary to general belief, attacks rarely consist of intermittent severe pains coming and going every few minutes.
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Subsequent to an attack of renal colic there may be intermittent dull pain in the loin or back. It is therefore often suspected that such pains in patients who have not had renal colic may be related to renal stones. Unfortunately, this is frequently not the case, and it is presumed that in most cases this discomfort is musculoskeletal in origin.
Investigations
The diagnosis of renal colic is usually made easily from the history and by finding red cells in the urine. Any patient suspected of having stones should have investigations to identify the site of the stone and degree of obstruction. About 90% of stones are seen on a plain abdominal radiograph. When the stone is in the ureter an IVU shows delayed excretion of contrast from the kidney and a dilated ureter down to the stone (see Fig. 14.38). IVU is very accurate and remains the most commonly used investigation world-wide, but spiral CT gives the most accurate assessment and will identify non-opaque stones (e.g. uric acid).
Patients with a first renal stone should have a minimum set of investigations; the yield of more detailed investigation is low, and hence usually reserved for those with recurrent or multiple stones, or those with complicated or unexpected presentations (e.g. in the very young; see Box 14.36).


Figure 14.38 Unilateral obstruction. Intravenous urogram of a patient with a stone (not visible) at the lower end of the right ureter. This film, taken 2 hours post-contrast injection, demonstrates persistence of contrast medium in the right kidney, pelvicalyceal system and ureter, whereas only a small amount remains visible in the normal left pelvicalyceal system.
14.36 INVESTIGATIONS FOR RENAL STONES
Sample Test First stone Recurrent stones
Stone Chemical composition-most valuable when possible v v
Blood Calcium v v
Phosphate v v
Uric acid v v
Urea and electrolytes v v
Parathyroid hormone-only if calcium or calcium excretion high (v)
Urine Dipstick test for protein, blood, glucose v v
Amino acids v
24-hr
urine Urea v
Creatinine clearance v
Sodium v
Calcium v
Oxalate v
Uric acid v

Management
The immediate treatment of renal pain or renal colic is bed rest, and application of warmth to the site of pain. Renal colic is often unbearably painful and demands powerful analgesia, e.g. morphine (10-20 mg), pethidine (100 mg) intramuscularly or diclofenac as a suppository (100 mg). Patients are advised to drink 2 litres per day. Around 90% of stones less than 4 mm in diameter will pass spontaneously but only 10% of stones of more than 6 mm will pass and may require active intervention. Immediate action is required if anuria or severe infection occurs in the stagnant urine proximal to the stone (pyonephrosis).
While attempts to dissolve stones have failed, most can now be fragmented by extracorporeal shock wave lithotripsy (ESWL; see Fig. 14.39). Using this apparatus shock waves generated outside the patient's body are focused on to the stone, breaking it into small pieces which can pass easily down the ureter. The technique requires free drainage of the distal urinary tract.
Endoscopic surgery is still often required for stones but open surgery is now almost never needed except for large bladder stones (see Box 14.37). All stones are potentially infected and surgery should be covered with appropriate antibiotics.
14.37 OPERATIVE INTERVENTION IN STONE DISEASE
Obstructive anuria or severe infection (pyonephrosis) ? Emergency percutaneous nephrostomy only
Severe pain or solitary kidney ? Urgent ESWL or surgery
Pain and failure of the stone to move ? Elective ESWL or surgery


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Figure 14.39 Surgical options for urinary stones.
14.38 GENERAL MEASURES TO PREVENT CALCIUM STONE FORMATION
Diet
Fluid-at least 2 l output per day (intake 3-4 l)-check with 24-hr urine collections-with intake distributed throughout the day (especially before bed)
Sodium-restrict intake
Protein-moderate; not high
Calcium-plenty in diet (because calcium forms an insoluble salt with dietary oxalate, lowering oxalate excretion) but avoid supplements away from meals (increase calcium excretion without reducing oxalate excretion)
Oxalate-avoid foods that are very rich in oxalate (e.g. rhubarb)
N.B. Citrate supplementation of unproven value.
Drugs
Thiazide diuretics-reduce calcium excretion; valuable in recurrent stone formers and patients with hypercalciuria
Allopurinol-if urate excretion high
Avoid (or carefully monitor) vitamin D supplements as they increase calcium absorption and excretion


Management to prevent further stone formation should be guided by the results of the investigations in Box 14.36, but some general principles apply to almost every patient with calcium-containing stones (see Box 14.38). More specific measures apply to some stone types. Urate stones can be prevented by allopurinol, and indeed this may also reduce calcium stone formation in patients with a high urate excretion. Stones formed in cystinuria can be reduced by penicillamine therapy. Attempts to alter urine pH with ammonium chloride (low pH discourages phosphate stone formation) or sodium bicarbonate (high pH discourages urate and cystine stone formation) may be made in the face of particular problems.

pages 632 - 634


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Home > 2 SYSTEM-BASED DISEASES > 14 Kidney and genitourinary disease > TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
TUMOURS OF THE KIDNEY
Tumours of the kidney account for 3% of all malignancies, and a variety of benign, malignant and secondary tumours can occur. Renal adenocarcinoma is by far the most common adult tumour, and nephroblastoma (Wilms' tumour) most common in children.
RENAL ADENOCARCINOMA
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This is the most common malignant tumour of the kidney in adults with an incidence of 16 cases per 100 000 population. It is twice as common in males as in females. The peak incidence is between 65 and 75 years of age and it is uncommon before 40. The tumour arises from renal tubules. Haemorrhage and necrosis give a characteristic mixed golden-yellow and red appearance to the cut surface. Microscopically, there are clear and granular cell types; the former are more common. There is early spread of the tumour into the renal pelvis, causing haematuria. Invasion of the renal vein, often extending into the inferior vena cava, also occurs early. Direct spread into perinephric tissues is common. Lymphatic spread occurs to para-aortic nodes, while blood-borne metastases (which may be solitary) may develop almost anywhere in the body.
Clinical features
About 60% of cases present with haematuria, 40% with loin pain and only 25% with a mass. The triad of pain, haematuria and a mass is an important but late feature occurring in only 15% of cases. A remarkable range of systemic effects may occur, including fever, raised ESR, polycythaemia, disorders of coagulation, and abnormalities of plasma proteins and liver function tests. The patient may present with pyrexia of unknown origin or, rarely, with neuropathy. Systemic effects may be due to tumour secretion of products such as renin, erythropoietin, parathormone and gonadotrophins. The effects disappear when the tumour is removed but may reappear when metastases develop, and so can be used as markers of tumour activity.
Investigations
The initial investigation is ultrasound, which allows differentiation between solid tumour and simple renal cysts. Thereafter, a contrast-enhanced CT of the abdomen and chest should be performed for staging (see Fig. 14.40).
Management and prognosis


Figure 14.40 Renal adenocarcinoma. In this CT, the right kidney is expanded by a low-density tumour which fails to take up contrast material. Tumour is shown extending into the renal vein and inferior vena cava (arrow).
Radical nephrectomy that includes the perirenal fascial envelope and ipsilateral para-aortic lymph nodes is performed whenever possible. Renal adenocarcinoma is resistant to radiotherapy and chemotherapy but some benefit has been seen with immunotherapy using interferon and interleukin-2. Even when metastases are present, nephrectomy should always be considered. Not only may systemic effects disappear, but there may even be regression of any metastases. Solitary metastases tend to remain single for long periods and excision is often worth while.
If the tumour is confined to the kidney, the 5-year survival is 75%. This falls to only 5% when there are distant metastases.
NEPHROBLASTOMA
Nephroblastoma is the most common childhood urological malignancy with an incidence of 7 per million children per year. It usually occurs in children under 4 years of age. The tumour is probably derived from embryonic mesodermal tissue and microscopically has a mixed appearance of spindle cells, epithelial cells and muscle fibres. Growth is rapid and there is early local spread, including invasion of the renal vein. Invasion of the renal pelvis occurs late, so haematuria is seen in only 15% of cases. Distant metastases most commonly appear in the lungs, liver and bones. Tumours presenting in the first year of life have a better prognosis.
Clinical features
The cardinal sign is a large abdominal mass. Some of the unusual clinical features associated with a renal carcinoma in adults, such as fever or hypertension, may be present.
Investigations
A CT of the abdomen and chest is essential for diagnosis and staging. The main differential diagnosis is from a neuroblastoma affecting the adrenal, but other causes of a large kidney, such as hydronephrosis and cystic disease, must be considered. The tumour is bilateral in 5-10% of cases.
Management
Transabdominal nephrectomy with wide excision of the mass is carried out after preliminary ligation of the renal pedicle. This is followed by chemotherapy using dactinomycin and vincristine. Radiotherapy is reserved for residual disease. As a result of this treatment, the 5-year survival rate has improved from 10% to 80%.
TUMOUR SYNDROMES
Two uncommon autosomal dominant inherited conditions are associated with the formation of multiple renal tumours in adult life. In tuberous sclerosis (see p. 1097) replacement of renal tissue by multiple angiomyolipomas (tubers) may occasionally cause renal failure in adult life. Other organs affected include the skin (adenoma sebaceum on the face) and brain (causing seizures and mental retardation). The von Hippel-Lindau syndrome (see p. 1207) is associated with the formation of multiple renal cysts, renal adenomas and renal adenocarcinoma. Other organs affected include the CNS (haemangioblastomas) and the adrenals (phaeochromocytoma).
TUMOURS OF THE RENAL PELVIS, URETERS AND BLADDER
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The vast majority of these tumours arise from the urothelium or transitional cell lining. The urothelium is exposed to chemical carcinogens excreted in the urine such as naphthylamines and benzidine which were extensively used in the chemical and dye industries until their carcinogenic properties were recognised. The bladder is more susceptible to urinary carcinogens as urine is stored in the bladder for relatively long periods of time. Almost all tumours are transitional cell carcinomas. Squamous carcinoma may occur in urothelium that has undergone metaplasia, usually due to chronic inflammation or irritation due to a stone or schistosomiasis.
The incidence of transitional cell carcinoma in the bladder in the UK is 45 cases per 100 000 population, and is three times more common in men than women. The appearance of a transitional cell tumour ranges from a delicate papillary structure to a solid ulcerating mass (see Fig. 14.41). The appearance correlates well with subsequent behaviour, in that papillary tumours are relatively benign cancers while those which ulcerate are much more aggressive.


Figure 14.41 Transitional cell carcinoma of the bladder. Stages are shown from carcinoma in situ (Cis) to invasive tumour progressing beyond the bladder and prostate (T4b).
Clinical features
More than 80% of patients have haematuria, which is usually visible and painless. It should be assumed that such bleeding is from a tumour until proved otherwise. A tumour at the lower end of a ureter or a bladder tumour involving the ureteric orifice may cause obstructive symptoms. Examination is usually unhelpful. Rectal examination detects only very advanced tumours.
Investigations
Imaging of the whole of the urinary tract is essential; when the bleeding is macroscopic this is best performed by IVU. If there is any suspicious defect in the ureter or renal pelvis, a retrograde ureteropyelogram is required. Cystoscopy is mandatory as small bladder tumours are easily missed on IVU. Solid invasive tumours need to be staged by CT of the abdomen, pelvis and chest. Microscopic haematuria carries a lower risk of malignancy, and a common strategy is to undertake flexible cystoscopy, ultrasound examination (rather than IVU) and urine cytology, and perform a plain radiograph of the kidneys, ureters and bladder.
Management
Small, large and even multiple superficial bladder tumours can be treated endoscopically by transurethral resection of the tumour(s) (TURT). Intravesical chemotherapy (e.g. epirubicin, mitomycin C) is useful to treat multiple low-grade bladder tumours and to reduce their recurrence rate. Regular 'check' cystoscopies are required and recurrences can usually be controlled by diathermy; only rarely will cystectomy be required for superficial disease.
Carcinoma in situ (Cis) may occur in association with a proliferative tumour (often in an apparently normal mucosa), or as a separate entity, when there may be only a generalised redness (malignant cystitis). Untreated patients with Cis have a high risk of progression to invasive cancer. The tumour responds well to intravesical bacille Calmette-Guérin (BCG) treatment but if there is any doubt about the response, and especially if there is any pathological evidence of progression, more aggressive treatment is needed (see below).
The management of invasive bladder tumours is debated. Radical cystectomy is recommended for patients under 70 years of age. The morbidity and mortality associated with such a radical procedure increase with age and radical radiotherapy may be a better option in older patients. Unfortunately, this may not always cure the tumour and 'salvage' cystectomy may be needed for recurrence or for symptoms such as intractable bleeding.
Cystectomy necessitates urinary diversion. In favourable cases, however, where the urethra can be retained, it may be possible to construct a new bladder from colon or small bowel (orthotopic bladder replacement). In such cases the patient may retain normal continence. Alternatively, a continent urinary diversion can be constructed. In less favourable circumstances an ileal conduit should be performed. In some countries where a stoma is not acceptable, the ureters can be implanted into the sigmoid colon (ureterosigmoidostomy), but renal infection and metabolic disturbances can be serious complications.
Transitional cell carcinoma of the renal pelvis and ureter is usually treated by nephroureterectomy and regular surveillance of the bladder, but if the tumour is solitary and low-grade it may be treated endoscopically; surveillance remains problematic.
Prognosis
The prognosis of bladder tumours depends on tumour stage and grade. The 5-year survival rate varies from 50-60% in those with superficial tumours to 20-30% for those with deep muscle invasion. Overall, about one-third of patients survive for 5 years.
PROSTATIC DISEASE
BENIGN PROSTATIC HYPERPLASIA
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From 40 years of age the prostate increases in volume by 2.4 cm3 per year on average. The process begins in the periurethral (central) zone of the prostate and involves both glandular and stromal tissue to a variable degree. Associated symptoms are common from 60 years, and some 50% of men over 80 years of age will have lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH).




Integration link: Benign prostatic hypertrophy - etiology and pathogenesis

Taken from Robbins & Cotran's Pathologic Basis of Disease 7e




Clinical features
The primary symptoms of BPH are due to the prostate obstructing the urethra and consist of hesitancy, poor prolonged flow and a sensation of incomplete emptying. Secondary (irritative) symptoms comprising urinary frequency, urgency of micturition and urge incontinence are not specific to BPH.
Patients may present more dramatically with acute urinary retention where they are suddenly unable to micturate and develop a painful distended bladder. This is often precipitated by excessive alcohol intake, constipation or prostatic infection. This is an emergency and requires the bladder to be drained by a catheter to relieve the retention. In chronic retention the bladder slowly distends due to inadequate emptying over a long period of time. This condition is characterised by pain-free bladder distension; this may cause back pressure on the kidneys over a prolonged time and result in hydroureter, hydronephrosis and renal failure. Patients with chronic retention can also develop acute retention: so-called acute on chronic retention. They require careful management because of their renal failure.
Investigations
Symptoms are scored on the international prostate symptom score (IPSS, see Box 14.39) which serves as a valuable starting point for the assessment of urinary problems. Once a baseline value is established any improvement/deterioration may be assessed on subsequent visits. Flow rates are accurately measured with a flow meter and prostate volume can be estimated by rectal examination or more accurately by transrectal ultrasound scan (TRUS). Assessment of obstruction is only possible by urodynamics (see Fig. 14.13, p. 593).
Management
14.39 DETERMINING THE INTERNATIONAL PROSTATE SYMPTOM SCORE (IPSS): A WORKING EXAMPLE FOR A PATIENT WITH MODERATE SYMPTOMS
IPSS Not at all Less than 1 time in 5 Less than half the time About half the time More than half the time Almost always Your score
1. Straining 0 1 [cir2] 3 4 5
2. Weak stream 0 1 [cir2] 3 4 5
3. Intermittency 0 1 [cir2] 3 4 5
4. Incomplete emptying 0 1 [cir2] 3 4 5
5. Frequency 0 1 [cir2] 3 4 5
6. Urgency 0 1 [cir2] 3 4 5
7. Nocturia (times per night) 0 [cir1] 2 3 4 5
Total IPSS score 13
Delighted Pleased Satisfied Mixed Dissatisfied Unhappy Terrible
Quality of life 0 1 2 [cir3] 4 5 6


Key Scores: 0-7 = mild symptoms; 8-19 = moderate symptoms; 20-35 = severe symptoms.
EBM
BENIGN PROSTATIC HYPERPLASIA-role of medical management
'Oral a-adrenoceptor blocker therapy causes prostatic relaxation and rapid improvement in urinary flow in 60-70% of patients. The 5a-reductase inhibitor finasteride causes slow shrinkage of large prostate glands with improvement in symptoms.'
Caine M, Perlberg S, Meretyk S. A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction. Brit J Urol 1978; 50:551-554.
Clifford GM, Farmer RD. Medical therapy for benign prostatic hyperplasia: a review of the literature. Eur Urol 2000; 38:2-19.
Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostate hyperplasia with finasteride: meta-analysis of randomised clinical trials. Urology 1996; 48:398-405.
Further information: www.cochrane.co.uk

14.40 TREATMENT FOR BENIGN PROSTATIC HYPERTROPHY
Medical
Prostate < 40 cm3 a-adrenoceptor blockers
Prostate > 40 cm3 finasteride (5a-reductase inhibitor)
Non-surgical intervention
Thermotherapy
Surgical
TURP
Holmium laser enucleation
Open prostatectomy


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Mild to moderate symptoms can be treated by medication (see EBM panel and Box 14.40). Alpha-adrenoceptor blockers (e.g. alfuzosin, tamsulosin) reduce the tone in the prostate, thereby reducing the obstruction. Finasteride (a 5a-reductase inhibitor) stops the conversion of testosterone to dihydrotestosterone in the prostate and so causes the prostate to shrink. Severe symptoms require surgical removal of some of the obstructing prostate tissue. Transurethral resection of the prostate (TURP) still remains the gold standard treatment but enucleation of the prostate by holmium laser appears as effective with potentially fewer complications. Open surgery is rarely required except in very large glands (> 100 cm3). Thermotherapy, where the prostate is heated by microwaves of radio frequency through a urethral catheter, is little better than medication but may have a place in the patient unfit for surgery.
PROSTATE TUMOURS
Prostatic cancer is common in northern Europe and the US (particularly in the black population) but rare in China and Japan. In the UK it is the third most common malignancy in males, with an incidence of 50 cases per 100 000 population and increasing in frequency. It is the second most common cause of cancer death in men in the UK. It rarely occurs before the age of 50 and is uncommon before the age of 60. The mean age at presentation is 70 years. The aetiology is unknown.
Prostate cancers arise within the peripheral zone of the prostate and almost all are carcinomas. Metastatic spread to pelvic lymph nodes occurs early and metastases to bone, mainly the lumbar spine and pelvis, are common. Prostatic specific antigen (PSA) is a good tumour marker for this malignancy and 40% of patients with a serum PSA > 4.0 ng/ml will have prostate cancer on biopsy. This has led to the introduction of screening programmes, principally in the USA, despite a lack of consensus about their utility.




Integration link: Prostatic carcinoma

Taken from Robbins & Cotran's Pathologic Basis of Disease 7e




Clinical features
Most patients present with lower urinary tract symptoms indistinguishable from BPH. Symptoms and signs due to metastases are much less common and include back pain, weight loss, anaemia and obstruction of the ureters. On rectal examination the prostate feels nodular and stony hard, and the median sulcus may be lost. However, 10-15% of tumours are not palpable.
Investigations
Since most patients present with outflow tract obstruction, an ultrasound scan and serum creatinine determination are used to assess the urinary tract. A plain radiograph of the pelvis and lumbar spine (to investigate backache) may show osteosclerotic metastases as the first evidence of prostatic malignancy.
Whenever possible, the diagnosis is confirmed by needle biopsy, usually aided by transrectal ultrasound scan (see Fig. 14.42), or by histological examination of tissue removed by endoscopic resection if this is needed to relieve outflow obstruction.
The patient is assessed for distant metastases by a radioisotope bone scan but high levels of serum PSA (> 100 ng/ml) almost always indicate distant bone metastases. PSA is also useful for monitoring response to treatment and disease progression.
Management
Tumour confined to the prostate is potentially curable by either radical prostatectomy or radical radiotherapy, and these options should be considered in all patients with more than 10 years' life expectancy. A small focus of tumour found incidentally at TURP does not significantly alter life expectancy and only requires follow-up.


Figure 14.42 Transrectal ultrasound of the prostate (TRUS) and needle biopsy. Scanning alone will miss 40% of cancers and biopsy is mandatory.
Approximately half of the men with prostate cancer will have metastatic disease at the time of diagnosis. Prostatic cancer, like breast cancer, is sensitive to hormonal influences; locally advanced or metastatic prostate cancer is treated by androgen depletion either by surgery (orchidectomy) or more commonly now by androgen-suppressing drugs (see EBM panel). Anti-androgen drugs such as cyproterone acetate act by preventing dihydrotestosterone binding to the tumour cells, so preventing cell growth. Luteinising hormone-releasing hormone analogues such as goserelin act by binding irreversibly to pituitary receptors. This initially causes an increase in testosterone before producing a prolonged reduction, and for this reason the initial dose must be covered with an anti-androgen to prevent a tumour flare.
EBM
PROSTATE CANCER-role of hormone manipulation in treatment
'Prostate cancer is hormone-sensitive, and reducing circulating testosterone levels to castrate levels (either by castration or by medication) results in a 70% initial response rate. Further reduction by blocking adrenal testosterone (maximal androgen blockade) produces a small but significant increase in survival but with poorer quality of life.'
Huggins C, Hodges CV. Studies on prostate cancer: the effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293-297.
Schmitt B, Bennett C, Seidenfeld J, et al. Maximal androgen blockade for advanced prostate cancer (Cochrane Review). Cochrane Library, issue 4, 2000. Oxford: Update Software.
Further information: www.cochrane.co.uk

A small proportion of patients fail to respond to endocrine treatment. A larger number respond for a year or two, but then the disease progresses. Other oestrogens or progesterones are of limited value but chemotherapy with 5-fluorouracil, cyclophosphamide or nitrogen mustard can be effective. Radiotherapy is useful treatment for localised bone pain. For severe generalised bone pain, hemi-body radiotherapy, or 89strontium may give effective palliation but the basis of treatment remains pain control by analgesia (see p. 228).
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Prognosis
The life expectancy of a patient with an incidental finding of focal carcinoma of the prostate is that of the normal population. With tumours localised to the prostate, a 10-year survival rate of 50% can be expected, but if metastases are present this falls to 10%.
TESTICULAR TUMOURS
Tumours of the testes are uncommon, with an incidence of 5 cases per 100 000 population, but they occur in men between the age of 20 and 40 years. These tumours secrete tumour markers which provide good indices for both diagnosis and prognosis. Seminoma and teratoma account for 85% of all tumours of the testis.
Seminomas arise from seminiferous tubules and represent a relatively low-grade malignancy. Metastases occur mainly via the lymphatics and may involve the lungs. Teratomas arise from primitive germinal cells. They may contain cartilage, bone, muscle, fat and a variety of other tissues, and are classified according to the degree of differentiation. Well-differentiated tumours are the least aggressive; at the other extreme, trophoblastic teratoma is highly malignant. Occasionally, teratoma and seminoma occur together.
Clinical features
The common presentation is incidental discovery of a painless testicular lump although some patients complain of a testicular ache. The peak age for a teratoma is 20-30 years and for a seminoma 30-40 years, but either may occur at any age.
Investigations
All suspicious scrotal lumps should be imaged by ultrasound which provides a high degree of accuracy. As soon as a tumour is suspected, and before orchidectomy, serum levels of alphafetoprotein (AFP) and ß-human chorionic gonadotrophin (ß-HCG) should be determined. The levels of these 'tumour markers' are increased in extensive disease. Accurate staging is based on CT of the lungs, liver and retroperitoneal area, and renal and pulmonary function should be assessed.
Management
Through an inguinal incision the cord is ligated and divided at the internal ring, and the testis is removed. Subsequent treatment depends on the histological type and stage. Radiotherapy is the treatment of choice for early stage seminoma since this tumour is very radiosensitive. The management of a teratoma depends on the stage of the disease. Early disease confined to the testes may be managed without further treatment provided that there is close surveillance for at least 2 years; tumour progression is treated by chemotherapy. More advanced cancers are managed initially by chemotherapy, usually the combination of bleomycin, etoposide and cisplatin. Follow-up is by CT and assessment of AFP and ß-HCG. Retroperitoneal lymph node dissection is now only performed for residual or recurrent nodal masses.
Prognosis
The 5-year survival rate for patients with seminoma is 90-95%. The more variable prognosis of teratomas depends on tumour type, stage and volume. With more favourable tumours the 5-year survival rate may be as high as 95%, but in more advanced cases 60-70% is more usual.
FURTHER INFORMATION
Bihl G, Meyers A. Recurrent renal stone disease-advances in pathogenesis and clinical management. Lancet 2001; 358:651-656. Medline Similar articles Full article
Brater DC. Drug therapy: diuretic therapy. N Engl J Med 1998; 339:387-395. Review articles. Medline Similar articles Full article
Bushinsky DA. Nephrolithiasis. Am J Kidney Dis 1998; 9:917-924.
Davison JM. Management of pre-existing disorders in pregnancy: renal disease. Prescribers' Journal 1997; 37:46-53.
Johnson RJ, Feehally JF, eds. Comprehensive clinical nephrology. London: Harcourt Brace; 1999.
Short A, Cumming AD. ABC of intensive care: renal support. BMJ 1999: 319:41-44.
Walker R. General management of end-stage renal disease. BMJ 1997; 315:1429-1432.
www.edren.org Website of the Renal Unit, Royal Infirmary of Edinburgh; information about individual diseases, protocols for immediate in-hospital management and a list of educational resources, including key cases; extensive links to other resources.
www.nephron.com The links under 'professional resources' are particularly good and include useful urology links; includes an MDRD calculator for estimating GFR from serum creatinine; extensive links to other resources.
www.sign.ac.uk Scottish Intercollegiate Guidelines Network; management of haematuria, proteinuria, diabetic renal disease.
www.sin-italia.org/imago/sediment/sed-htm Italian Society of Nephrology website; analysis of urinary sediment.

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